U.S. patent application number 12/056393 was filed with the patent office on 2008-10-02 for process for preparing epothilone derivatives by selective catalytic epoxidation.
Invention is credited to Orlin Petrov, Johannes PLATZEK, Stephan Pruhs.
Application Number | 20080242868 12/056393 |
Document ID | / |
Family ID | 39551678 |
Filed Date | 2008-10-02 |
United States Patent
Application |
20080242868 |
Kind Code |
A1 |
PLATZEK; Johannes ; et
al. |
October 2, 2008 |
PROCESS FOR PREPARING EPOTHILONE DERIVATIVES BY SELECTIVE CATALYTIC
EPOXIDATION
Abstract
The present invention describes a novel process for preparing an
epothilone derivative using substituted pyridines and
methyltrioxorhenium as catalyst.
Inventors: |
PLATZEK; Johannes; (Berlin,
DE) ; Petrov; Orlin; (Berlin, DE) ; Pruhs;
Stephan; (Neuss, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
39551678 |
Appl. No.: |
12/056393 |
Filed: |
March 27, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60907415 |
Apr 2, 2007 |
|
|
|
Current U.S.
Class: |
548/180 |
Current CPC
Class: |
C07D 417/04 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
548/180 |
International
Class: |
C07D 277/62 20060101
C07D277/62 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 30, 2007 |
DE |
10 2007 016 046.3 |
Claims
1. Process for preparing the epothilone derivative of the formula
(I) ##STR00013## characterized in that the dialkene of the formula
(II) ##STR00014## is epoxidized using methyltrioxorhenium with an
epoxidizing agent in an aprotic solvent at -60.degree. C. to
-20.degree. C.
2. Process according to claim 1, in which the epoxidizing agent is
aqueous hydrogen peroxide solution.
3. Process according to claim 1, in which there is further addition
of a substituted pyridine derivative.
4. Process according to claim 3, characterized in that the dialkene
of the formula (II) is reacted at -60 to -20.degree. C. in
chlorinated hydrocarbons or mixtures thereof with low-boiling
alkanes or toluene or trifluorotoluene as solvent using 6-36 mol %
of a substituted pyridine, and 1-7 mol % methyltrioxorhenium and
2-5 equivalents 10-60% strength aqueous hydrogen peroxide
solution.
5. Process according to claim 1, where the reaction times are
between 20-120 h.
6. Process according to claim 1, where the concentration of the
compound of the formula II is in the range from 1 g in 5 ml of
solvent to 1 g in 50 ml of solvent.
7. Process according to claim 1, characterized in that the solvent
is selected from the group of dichloromethane, 1,2-dichloroethane,
chloroform, and mixtures thereof with pentane, hexane, heptane,
cyclohexane, toluene or trifluorotoluene, or toluene or
trifluorotoluene on their own.
8. Process according to claim 3, characterized in that the
substituted pyridine is selected from the group ##STR00015##
9. Process according to claim 3, characterized in that the
substituted pyridine is an electron-poor pyridine derivative which
is substituted in position 4 by CN, Br, Cl, F, CF.sub.3,
SO.sub.2(C.sub.1-C.sub.4)alkyl, SO.sub.2NH.sub.2,
SO.sub.2N[(C.sub.1-C.sub.4)alkyl].sub.2, COOH,
COO(C.sub.1-C.sub.4)alkyl.
10. Epothilone derivative of the formula I prepared by the process
according to claim 1 containing rhenium.
11. Epothilone derivative according to claim 10, containing 0.01 to
30 ppm rhenium.
12. Process according to claim 1, characterized in that the crude
product obtained is crystallized.
Description
[0001] This application claims the benefit of the filing date of
U.S. Provisional Application Ser. No. 60/907,415 filed Apr. 2,
2007.
[0002] The invention relates to the subject-matter characterized in
the claims, that is to say a novel selective epoxidation process
for preparing the epothilone derivative of the formula I. The
process of the invention affords the target compound of the formula
I in high chemical and diastereomeric purity, very good yields and
permits preparation on a large scale.
[0003] Hofle et al. described the cytotoxic effect of the natural
products epothilone A (R=hydrogen) and epothilone B (R=methyl)
##STR00001## [0004] epothilone A (R.dbd.H), epothilone B
(R.dbd.CH.sub.3) e.g. in Angew. Chem. 1996, 108, 1671-1673.
Epothilones are representatives of a class of promising antitumour
agents which have been tested as potent against a number of cancer
lines. An overview of the syntheses have been described for example
by J. Mulzer in Monatsh. Chem. 2000, 131, 205-238. These agents
display the same biological mechanism of action as paclitaxel and
other taxanes (concerning paclitaxel, see D. G. I. Kingston, Chem,
Commun. 2001, 867-880). Epothilones differ from the latter by being
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).
[0005] Because of the in vitro selectivity in relation to breast
and bowel cell lines and their distinctly higher activity, compared
with Taxol, against p-glycoprotein-forming, multiresistent tumour
lines, and their improved physical properties, compared with Taxol,
e.g. a solubility in water which is a factor of 30 higher, this
novel structural class is of particular interest for developing a
medicament for the therapy of malignant tumours.
[0006] A whole series of synthetically modified epothilone
derivatives have been prepared, including those having an aromatic
or heteroaromatic group in position 1 instead of the
methylthiazole-methylvinyl side chains.
[0007] Epothilone derivatives with fused aromatic heterocycles in
position 1 are disclosed in the patent literature, e.g. by Schering
AG, WO 00/66589 and Novartis WO 2000/037473. Since these compounds
are very potent antitumour agents, it is of great interest to have
an economic and efficient synthesis of this structural class
available.
[0008] Among the compounds described in the Schering application WO
00/66589, compound (I) was particularly notable:
##STR00002##
[0009] Because of the outstanding data from animal experiments,
this compound was selected for development. The compound is
currently undergoing clinical trials. The synthesis is described in
Angewandte Chemie, Int. Ed. (2006), 45 (47), 7942.
[0010] There was a great need for a selective method for
epoxidizing the trisubstituted double bond in position 12,13
##STR00003##
because there is observed to be with the processes described in the
prior art (see below) firstly a relatively moderate selectivity
(averaging 7-10:1 alpha/beta epoxide) and an additional attack of
the epoxidizing reagent on the exo double bond. Epoxidation of the
exo double bond leads in an immediately following reaction to the
unwanted impurities mentioned below (IIIa+IIIb). These impurities
may arise from the product of the formula I (by overoxidation) or
else even from the alkene II:
##STR00004##
[0011] Because of the moderate selectivity of the epoxidation
methods described, the reaction mixture contains besides the target
compound I also the beta isomer (Ia), from which corresponding
impurities likewise arise in an analogous manner. Removal of all
these by-products is time-consuming and takes place by difficult,
elaborate and costly chromatography.
[0012] Numerous methods for epoxidizing epothilones have now been
published. The epoxidizing agents described in the literature for
epoxidizing epothilone derivatives are substantially those
mentioned below:
TABLE-US-00001 Yields Reagent Literature (selectivities) DMDO JACs,
2001, 5407 78% (2,2-Dimethyldioxirane) JACS 2000, 10521 97%
Tetrahedron Lett. 2001, 6785 100% JACS, 1999, 7050 80% Angewandte
Chemie, 1998, 98% 2821 JOC, 1999, 684 78% 2-Trifluoromethyl-2-
Chem. Comun. 1997, 2343 20%/55% methyldioxirane Chem. Eur. J.,
1997, 1971 76% (8:1) Review on the reagent: 60% (2:1) Acc. Chem.
Rev. 2004, JACS, 2001, 5249 60% 37, 497-505 Org. Lett. 2001, 3607
56% JACS, 1997, 7974 85% (5:1) MCPBA JACS, 1997, 7974 66% (5:1)
(Meta-chloroperbenzoic Chem. Europ. J. 1997, 1971 34%/38% acid)
Org. Biomol. Chem. 2004, 127 55% Org. Lett. 2001, 2221 65% Shi
catalyst/Oxone Angew. Chem. 2005, 117, 7636 65% (5:1) Review:
synthesis, 2000, Application to ZK EPO starting 63% (5:1) No. 14,
1979-2000 from dialkene II Acc. Chem. Res. 2004, 37, 488-496
Methyltrioxorhenium Angew. Chem. 2005, 117, 7636 9-10:1 (MTO) and
Bioorganic Med. Chem. 10 (2000), 2765
[0013] All these reagents have the disadvantage that, besides a
poor .alpha./.beta. selectivity on the epoxide, there is also
extensive attack on the exo double bond (in some cases >>5%),
which means that the regioselectivity is also unsatisfactory.
Extensive losses of yield in the last stage of the synthesis are
the result. Since the dialkene (II) itself is very valuable, having
been prepared over many stages, the loss of every percent of
product in the last step is very uneconomic.
[0014] The only practicable method, which has also been transferred
to the pilot-plant scale, is the use of dimethyldioxirane (DMDO in
acetone) at low temperature and high dilution:
##STR00005##
[0015] Although relatively high yields are described in many
publications (see above), this method is unsatisfactory for our
substrate, however. The selectivities achieved in this process were
7-7.6:1 (.alpha./.beta.), and the yields after isolation of the
pure compound in the laboratory (small batches) were 71% of theory
(after chromatography and crystallization), but were only 64% of
theory on the operational scale.
[0016] The use of MTO as epoxidation catalyst, also in combination
with a wide variety of pyridine derivatives, has been known per se
for a long time: [0017] Chem. Eur. J. 2002, 8, No. 13, 3053 [0018]
Chem. Commun. 200, 1165 [0019] Tetrahedron Letters 40 (1999), 3991
[0020] JACS 1997, 119, 11536 [0021] JACS 1997, 119, 6189 [0022]
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 12, 1638 [0023] JOC 2000,
65, 5001 and 8651 [0024] J. Organometallic Chemistry 555 (1998),
293 [0025] JACS 1998, 120, 11335 [0026] Monograph: "Aziridines and
Epoxides in Organic Synthesis", Andrei K. Yudin, Wiley-VCH Verlag
GmBH & Co. KGaA 2006, pp. 185-228, and the literature cited
therein.
[0027] However, the reaction is in most cases carried out at room
temperature. It is possible to epoxidize both tri- and di- and
monosubstituted double bonds using this method.
[0028] However, diastereoselective epoxidations with high
selectivities (e.g. on natural products, e.g. of the epothilone
type) are not described.
[0029] Two publications by Altmann (Angew. Chem. 2005, 117, 7636
and Bioorg. Med. Chem. Lett. 10 (2000), 2765) describe the use of
catalytic amounts of methyltrioxorhenium (MTO) in combination with
pyridine and hydrogen peroxide (as oxygen source).
[0030] These publications by Altmann describe the first application
of the MTO reagent for the selective preparation of
epothilones:
##STR00006##
[0031] The examples described in these publications contain no
additional exo double bonds of the type in the compound of the
formula I, but in the case of epothilone B there is an additional
double bond which is conjugated with the thiazole ring. However, it
is known that this double bond is not attacked by other epoxidizing
reagents because of the lower electron density (electron-poor
double bond, because conjugated with the aromatic system). The
selectivities achieved are in a moderate range, at 9-10:1, with
yields of 37-72% of theory. The reactions are carried out at room
temperature and prolongation of the reaction time leads to losses
of yield.
[0032] No reactions with aqueous H.sub.2O.sub.2 at low temperatures
below -10.degree. C. are described in the prior art, because the
skilled person assumes that the reagent freezes under the
conditions and is no longer able to react.
[0033] However, we have now surprisingly found that reactions still
take place even at temperatures down to -60.degree. C., although
the reagent is present in the frozen state in the solution.
[0034] The attempt to use the Altmann method nevertheless for
preparing the compound of the formula I by, for example, lowering
the temperature was, however, unsatisfactory because the
selectivities were <10:1 (.alpha./.beta.) in all cases. In
addition, the above-mentioned impurities (about 2-4%) were likewise
observed. The following table shows the results obtained:
TABLE-US-00002 Reaction Temperature Conversion Selectivity time
-50.degree. C. 90% 9.8:1 12 h -40.degree. C. 96% 9.2:1 5 h
-30.degree. C. 99% 8.6:1 5 h -20.degree. C. 99% 7.4:1 3 h
-10.degree. C. 99% 6.7:1 3 h 0.degree. C. 99% 6.5:1 3 h RT
(20.degree. C.) 99% 5.1:1 3 h
[0035] The results show that the prior art methods are still
unsatisfactory for the synthesis of the epothilone derivatives of
the formula (I).
[0036] It was therefore the object to provide a novel method
permitting the epothilone derivative of the formula I to be
prepared with high .alpha./.beta. selectivity, high
regioselectivity, high purity of the crude product, and high yield
on the pilot scale so that elaborate chromatographic removal of the
by-products described above is avoided.
[0037] The present invention achieves this object and describes a
novel process for preparing this epothilone derivative of the
formula I starting from the dialkene of the formula II which is
likewise known from the literature
##STR00007##
which is obtained with high selectivity by epoxidizing the
trisubstituted double bond using methyltrioxorhenium in an aprotic
solvent at low temperature, in particular at -60.degree. C. to
-20.degree. C.
[0038] This surprisingly takes place particularly well on use of a
combination of methyltrioxorhenium (MTO) with substituted
pyridines, especially with 4-cyanopyridine.
[0039] Aqueous hydrogen peroxide solution especially in an aprotic
solvent at -60.degree. C. to -20.degree. C. is particularly
suitable as epoxidizing agent.
[0040] The compound of the formula (I) is obtained from the
dialkene of the formula II
##STR00008##
by reaction [0041] in an aprotic solvent, in particular a
chlorinated hydrocarbon, preferably dichloromethane or mixtures
thereof with low-boiling alkanes, trifluorotoluene or toluene as
solvent [0042] in concentrations of from 5-fold ("5-fold" means, 1
g of dialkene in 5 ml of solvent) to 50-fold (1 g of dialkene in 50
ml of solvent), preferably 5-20-fold, particularly preferably
10-fold, [0043] using 6-36 mol %, preferably 10-25 mol %,
particularly preferably 18 mol %, of a substituted pyridine,
preferably of an electron-poor substituted pyridine, particularly
preferably 4-CN-pyridine, [0044] and 1-7 mol % methyltrioxorhenium,
preferably 1-5%, particularly preferably 3 mol %, and [0045] 2-5
equivalents (eq.), preferably 3-4 eq., particularly preferably 3
eq., of 10-60% strength aqueous hydrogen peroxide solution,
preferably 30-35%, [0046] at reaction temperatures of from
-60.degree. C. to -20.degree. C., preferably at -55.degree. C. to
-35.degree. C., particularly preferably at -50.degree. C., [0047]
with reaction times of 20-120 h, preferably 40-100 h, particularly
preferably 50-90 h.
[0048] One embodiment of the invention represents the process
described above when all the first-mentioned conditions are
combined together: [0049] chlorinated hydrocarbons or mixtures
thereof with low-boiling alkanes or toluene or trifluorotoluene as
solvent, [0050] concentration of the dialkene 1 g/5 ml-50 ml [0051]
6-36 mol % of a substituted pyridine, [0052] 1-7 mol %
methyltrioxorhenium and [0053] 2-5 equivalents of a 10-60% strength
aqueous hydrogen peroxide solution.
[0054] A further embodiment relates to a process in which the
following conditions are combined together: [0055] chlorinated
hydrocarbons or mixtures thereof with low-boiling alkanes or
toluene or trifluorotoluene as solvent, [0056] concentration of the
dialkene 1 g/5 ml-50 ml [0057] 6-36 mol % of a substituted
pyridine, [0058] 1-7 mol % methyltrioxorhenium and [0059] 2-5
equivalents of a 10-60% strength aqueous hydrogen peroxide solution
[0060] reaction temperatures of -60.degree. C. to -20.degree. C.
and [0061] reaction times of 20-120 h.
[0062] One aspect of the invention represents the process described
above when the preferred conditions [0063] dichloromethane or
mixtures thereof with low-boiling alkanes, trifluorotoluene or
toluene as solvent [0064] concentration of the dialkene 1 g/5 ml-20
ml [0065] 10-25 mol % of an electron-poor substituted pyridine,
[0066] 1-5% methyltrioxorhenium, [0067] 3-4 equivalents of a 30-35%
strength aqueous hydrogen peroxide solution are combined
together.
[0068] A further embodiment of the invention represents the process
described above when all the preferred conditions are combined
together: [0069] dichloromethane or mixtures thereof with
low-boiling alkanes, trifluorotoluene or toluene as solvent [0070]
concentration of the dialkene 1 g/5 ml-20 ml [0071] 10-25 mol % of
an electron-poor substituted pyridine, [0072] 1-5%
methyltrioxorhenium, [0073] 3-4 equivalents of a 30-35% strength
aqueous hydrogen peroxide solution [0074] reaction temperatures of
-55.degree. C. to -35.degree. C. and [0075] reaction times of
40-100 h.
[0076] A further embodiment of the invention represents the process
described above when all the particularly preferred conditions are
combined together, the intention being if no particularly preferred
range is indicated that the preferred range is combined: [0077]
dichloromethane or mixtures thereof with low-boiling alkanes,
trifluorotoluene or toluene as solvent [0078] concentration of the
dialkene 1 g/10 ml [0079] 18 mol % of 4-CN-pyridine, [0080] 3 mol %
methyltrioxorhenium, [0081] 3 equivalents of a 30-35% strength
aqueous hydrogen peroxide solution, [0082] at reaction temperatures
of -50.degree. C. and [0083] reaction times of 50-90 h.
[0084] A particular embodiment of the invention is a process for
preparing the compound of the formula (I)
##STR00009##
when the dialkene of the formula (II)
##STR00010##
is reacted in dichloromethane as solvent in concentrations of 1 g
of dialkene in 10 ml of solvent, using 18 mol % 4-CN-pyridine, and
3% methyltrioxorhenium, and 3 eq of 10-60% strength aqueous
hydrogen peroxide solution, at reaction temperatures of from
-60.degree. to -20.degree. C. with reaction times of 50-90 h.
[0085] In a particularly preferred embodiment, the process is
carried out precisely under the conditions of Example 1.
[0086] One embodiment of the invention is one of the processes as
described above, in which the reaction temperature is -60.degree.
C. to -20.degree. C.
[0087] In one embodiment of the invention, the reaction takes place
at temperatures of from -55 to -35.degree. C.
[0088] A further embodiment is the process as described in claim 1,
in which the reaction times are between 20-120 h.
[0089] In one embodiment of the invention, the reaction times are
from 40 to 80 h.
[0090] In one embodiment of the invention the amount of
methyltrioxorhenium is 1-5 mol %, where the amount is based on the
dialkene.
[0091] A further embodiment is one of the processes as described
above, where the concentrations of the compound of the formula II
are from 1 g in 5 ml of solvent to 1 g in 50 ml of solvent.
[0092] A further embodiment is one of the processes as described
above, where the dialkene is present in concentrations of from 1 g
in 5 ml of solvent to 1 g in 20 ml of solvent.
[0093] It is also possible to use, instead of dichloromethane,
other solvents such as 1,2 dichloroethane, chloroform and mixtures
thereof with pentane, hexane, heptane, cyclohexane or other
low-boiling alkanes in various ratios, and aromatic solvents
(arylalkanes) such as, for example, toluene, trifluorotoluene. It
is also possible to employ dichloromethane mixed with the
abovementioned alkanes and arylalkanes.
[0094] Low-boiling alkanes mean straight-chain and branched alkanes
and cycloalkanes having boiling points of about 35.degree. C. to
100.degree. C.
[0095] In one embodiment of the invention, the solvent is selected
from the group of dichloromethane, 1,2-dichloroethane, chloroform,
and mixtures thereof with pentane, hexane, heptane, cyclohexane,
toluene or trifluorotoluene, or toluene or trifluorotoluene on
their own.
[0096] In one embodiment of the invention, the solvent is selected
from the group of mixtures of dichloromethane with pentane, hexane,
heptane, cyclohexane, toluene, or trifluorotoluene.
[0097] In a further embodiment of the invention, the solvent is
selected from the group of dichloromethane and mixtures of
dichloromethane with pentane, hexane, heptane, cyclohexane,
toluene, or trifluorotoluene.
[0098] Besides 4-cyanopyridine it is also possible to use as
alternative pyridine catalysts for example
##STR00011##
preferably
##STR00012##
[0099] In a further embodiment, 2- or 4-substituted electron-poor
pyridine derivatives substituted by CN, Br, Cl, F, CF.sub.3,
SO.sub.2 (C.sub.1-C.sub.4) alkyl, SO.sub.2NH.sub.2, SO.sub.2N
[(C.sub.1-C.sub.4) alkyl].sub.2, COOH, COO(C.sub.1-C.sub.4)alkyl,
in particular pyridines substituted by CN, Cl, F, SO.sub.2CH.sub.3,
COOH, COO(C.sub.1-C.sub.4)alkyl, are employed.
[0100] In a preferred embodiment, 4-substituted electron-poor
pyridine derivatives substituted by CN, Br, Cl, F, CF.sub.3,
SO.sub.2 (C.sub.1-C.sub.4) alkyl, SO.sub.2NH.sub.2, SO.sub.2N
[(C.sub.1-C.sub.4) alkyl].sub.2, COOH, COO(C.sub.1-C.sub.4)alkyl,
in particular pyridines substituted by CN, Cl, F, SO.sub.2CH.sub.3,
COOH, COO(C.sub.1-C.sub.4)alkyl, are employed.
[0101] 2- and 4-CN-pyridine is particularly preferred, and
4-CN-pyridine is very particularly preferred.
[0102] The term C.sub.1-C.sub.4-alkyl means straight-chain or
branched, for example methyl, ethyl, propyl, isopropyl.
[0103] In one embodiment of the invention, the amount of
substituted pyridine is 10-20 mol %, the amount being based on the
dialkene.
[0104] In one embodiment of the invention, 30-35% strength aqueous
hydrogen peroxide solution is employed.
[0105] In one embodiment of the invention, 3-4 equivalents of
hydrogen peroxide, based on the dialkene, are employed.
[0106] It has proved advantageous in some cases to replace hydrogen
peroxide by the urea-hydrogen peroxide complex (UHP) (Lit. Angew.
Chemie 1991, 103, 1706 and Angew. Chemie, 1996, 108, 578).
[0107] One embodiment of the invention therefore relates to a
process as defined in claim 1, where UHP is used as epoxidizing
agent.
[0108] For workup, a reducing agent known to the skilled person,
such as, for example, sodium thiosulphate, sodium sulphite, vitamin
C etc., is used to destroy the excess hydrogen peroxide, followed
by washing with water, and aqueous acidic solutions (for extractive
removal of the pyridine catalyst) of, for example, KHSO.sub.4,
H.sub.2SO.sub.4, HCl, phosphoric acid, methanesulphonic acid, TFA,
citric acid in water. A final wash with saturated aqueous NaCl
solution is possible where appropriate, followed by drying over
magnesium sulphate or sodium sulphate and then removal of the
solvent by distillation in vacuo. The residue is purified by
chromatography and then the compound of the formula (I) is finally
purified by crystallization and isolated. However, it can also be
filtered through a short layer of silica gel (removal of the
pyridine catalyst) and then be directly crystallized. The yields
achieved are 80-90%.
[0109] It is surprisingly possible to dispense with the
chromatographic purification and to employ the crude product
directly in the final crystallization.
[0110] The invention thus relates further to a process as described
in claim 1, which, after workup, is directly followed by a
crystallization.
[0111] The crude products obtained in the manner described above
already have very high purity. The reactions achieved are notable
for very high selectivities. In the case of a reaction temperature
of -50.degree. C. it was possible to obtain a selectivity of up to
57:1 (.alpha./.beta.) (see Example 1). The formation of the
by-products from exo attack on the double bond is virtually no
longer observed (total of impurities of this type: <0.1% in the
crude product).
[0112] The rhenium content of a compound of the formula I prepared
in this way is <<7 ppm (LOD*:7 ppm) (*level of detection;
method: ICP-OES). The detectability of amounts less than 7 ppm
depends on how large the amount of epothilone derivative there is
available for the measurement. A larger amount of epothilone
derivative means that a content of less than 7 ppm rhenium is more
likely to be detectable.
[0113] The occurrence of rhenium in the earth's crust is 0.0004
ppm, according to Rutherford online 2006.
[0114] Since the final product of the process of the invention may
still contain rhenium, a further aspect of the invention is also a
product of the process of the invention which still contains
rhenium.
[0115] One aspect of the invention is the product of the formula I
containing more than 0.0004 ppm rhenium.
[0116] In one embodiment, the final product contains >0.0004 ppm
to 7 ppm rhenium.
[0117] In a further embodiment, the final product contains
>0.0004 ppm to 1 ppm rhenium.
[0118] One aspect of the invention is the product of the formula I
containing rhenium in the range from 0.01 ppm to 30 ppm.
[0119] A further aspect of the invention is the product of the
formula I containing rhenium in the range from 0.1 ppm to 30
ppm.
[0120] In one embodiment, the reaction product contains from 1 ppm
up to 30 ppm rhenium.
[0121] In a further embodiment, the final product contains
.ltoreq.7 ppm to 30 ppm rhenium.
[0122] In a further embodiment, the final product contains 0.01 ppm
to 7 ppm rhenium.
[0123] In a further embodiment, the final product contains 0.01 ppm
to 1 ppm rhenium.
[0124] It has proved advantageous in some cases to employ instead
of the relatively pure dialkene II purified by chromatography, also
the crude product of this compound II directly in the epoxidation,
thus making it possible in an unexpected manner to increase the
overall yield of the two stages in total.
[0125] The novel process allows the compound of the formula (I) to
be prepared in high diastereselectivity and yield and purity. The
process is simple to operate and permits scaling-up into the
multi-kg range. It has the great advantage beside the methods
described in the prior art that no valuable substance is lost
through attack on the exo double bond. This process is therefore to
be categorized as a very practicable and economically valuable
method.
[0126] The following examples serve to illustrate the
subject-matter of the invention in more detail without intending to
restrict it thereto:
EXAMPLE 1
[0127] 1.000 kg of dialkene of the formula II (prepared according
to WO 00/66589), 14.17 g (3 mol %) of methyltrioxorhenium and 35.5
g (18 mol. %) of 4-cyanopyridine are dissolved in 10 litres of
dichloromethane and then cooled to -50.degree. C. 579 ml of 30%
strength aqueous hydrogen peroxide solution (3 eq.) are added, and
the mixture is stirred at -50.degree. C. for about 70 hours. The
reaction is followed by HPLC towards the end. Once precursor
(compound of the formula II) is below 1%, the reaction is quenched
by adding 580 ml of 20% strength aqueous sodium thiosulphate
solution. This is followed by addition of a further 7000 ml of
thiosulphate solution and warming to +10.degree. C. The mixture is
stirred at +10.degree. C. for one hour, the organic phase is
separated off, and the aqueous phase is back-extracted with 5000 ml
of dichloromethane. The combined organic phases are washed 5000 ml
of saturated aqueous sodium chloride solution. The organic phase is
concentrated in vacuo. The residue is filtered through a layer of
silica gel (mobile phase: dichloromethane/ethyl acetate gradient).
Yield: 877 g (85% of theory, .alpha./.beta.=57:1) of the compound
of the formula (I)
Recrystallization from hexane/toluene results in 824.3 g (80% of
theory based on II) of colourless crystals.
[0128] HPLC purity (100% method): 100%, no impurities >0.05% are
detected. The .beta. isomer has been completely removed Rhenium
content: <<7 ppm (LOD: 7 ppm)
Elemental analysis: Calc. C 66.27% H 7.60% N 2.58% S 5.90%
Found C 66.19% H 7.71% N 2.54% S 5.85%
Rotation:
[0129] [alpha].sub.D.sup.20: -73.2.degree. (c=0.514,
CHCl.sub.3).
[0130] .sup.1H NMR (300 MHz, CDCl.sub.3) delta=0.98 (3H), 1.02
(3H), 1.23 (3H), 1.25-1.78 (7H), 1.31 (3H), 2.15-2.31 (3H),
2.44-2.68 (4H), 2.84 (3H), 2.91 (1H), 3.60 (1H), 3.70 (1H), 4.20
(1H), 4.40 (1H), 5.01 (1H), 5.06 (1H), 5.73 (1H), 6.19 (1H), 7.36
(1H), 7.82 (1H), 7.94 (1H) ppm.
[0131] .sup.13C NMR (300 MHz, CDCl.sub.3) delta=219.7 (s, C-9),
170.5 (s, C-5), 168.2 (s, C-aryl), 153.5 (s, C-aryl), 137.2 (s,
C-aryl), 135.8 (d, .dbd.CH-allyl), 135.3 (s, C-aryl), 122.7 (d,
C-aryl), 121.7 (d, C-aryl), 119.7 (d, C-aryl), 117.1 (t,
.dbd.CH.sub.2-allyl), 77.0 (d, C-11), 74.3 (d, C-3), 74.3 (d, C-7),
60.9 (s, C-16), 60.0 (d, C-1), 52.2 (s, C-8), 51.3 (d, C-10), 38.6
(t, C-6), 34.8 (d, C-12), 34.3 (t, C-2), 34.1 (t, CH.sub.2-allyl),
31.3 (t, C-15), 29.6 (t, C-13), 22.5 (q, CH.sub.3 on C-8), 22.1 (t,
C-14), 22.1 (q, CH.sub.3 on C-16), 20.2 (q, CH.sub.3-aryl), 19.2
(q, CH.sub.3 on C-8), 17.9 (q, CH.sub.3 on C-12) ppm.
[0132] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The preceding preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0133] In the foregoing and in the examples, all temperatures are
set forth uncorrected in degrees Celsius and, all parts and
percentages are by weight, unless otherwise indicated.
[0134] The entire disclosures of all applications, patents and
publications, cited herein and of corresponding German application
No. 10 2007 016 046.3, filed Mar. 30, 2007 are incorporated by
reference herein.
[0135] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0136] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *