U.S. patent application number 10/803705 was filed with the patent office on 2004-09-09 for process for the preparation of indole derivatives and intermediates of the process.
Invention is credited to Wolleb, Annemarie, Wolleb, Heinz.
Application Number | 20040176614 10/803705 |
Document ID | / |
Family ID | 8174725 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040176614 |
Kind Code |
A1 |
Wolleb, Annemarie ; et
al. |
September 9, 2004 |
Process for the preparation of indole derivatives and intermediates
of the process
Abstract
A process for the preparation of compounds of formula 1 wherein
R.sub.1 is C.sub.1-C.sub.6alkyl and X is hydrogen, a hydrocarbon
radical or a cation, wherein a compound of formula 2 wherein
R.sub.1 is as defined above and R.sub.2 is hydrogen or a
hydrocarbon radical, is reduced, the resulting compound of formula
3 is reacted with a compound that introduces the radical of formula
--CH.sub.2--COOR.sub.3, wherein R.sub.3 has the meanings given
above for R.sub.2, and the resulting compound of formula 4 is
reduced and optionally hydrolysed.
Inventors: |
Wolleb, Annemarie; (Fehren,
CH) ; Wolleb, Heinz; (Fehren, CH) |
Correspondence
Address: |
CIBA SPECIALTY CHEMICALS CORPORATION
PATENT DEPARTMENT
540 WHITE PLAINS RD
P O BOX 2005
TARRYTOWN
NY
10591-9005
US
|
Family ID: |
8174725 |
Appl. No.: |
10/803705 |
Filed: |
March 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10803705 |
Mar 18, 2004 |
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10296106 |
Nov 22, 2002 |
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6743926 |
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10296106 |
Nov 22, 2002 |
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PCT/EP01/05667 |
May 17, 2001 |
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Current U.S.
Class: |
548/510 |
Current CPC
Class: |
C07D 209/24 20130101;
C07D 209/30 20130101 |
Class at
Publication: |
548/510 |
International
Class: |
C07D 209/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 26, 2000 |
EP |
00810460.6 |
Claims
What is claimed is:
1. A process for the preparation of a compound of formula 39wherein
R.sub.1 is C.sub.1-C.sub.6alkyl and X is hydrogen, a hydrocarbon
radical or a cation, wherein a compound of formula 40wherein
R.sub.1 is as defined above and R.sub.2 is hydrogen or a
hydrocarbon radical, is reduced, the resulting compound of formula
41wherein R.sub.1 and R.sub.2 are as defined above, is reacted with
a compound that introduces the radical of formula
--CH.sub.2--COOR.sub.3 wherein R.sub.3 has the meanings given above
for R.sub.2, and the resulting compound of formula 42is reduced and
optionally hydrolysed.
2. A process according to claim 1, wherein the compound of formula
(2) is obtained by reacting a compound of formula 43wherein R.sub.1
is as defined in claim 1 and Y is bromine, chlorine, iodine,
--OSO.sub.2CF.sub.3 or --COCl, especially bromine, with a compound
that introduces the radical of formula --CH.dbd.CH--Z, wherein Z is
the radical --COOR.sub.4, --COR.sub.5 or --CN, R.sub.4 is hydrogen
or a hydrocarbon radical and R.sub.5 is a hydrocarbon radical or
unsubstituted or substituted amino, and reacting the resulting
compound of formula 44optionally after conversion of the compound
of formula (6) wherein Z is the radical --COOR.sub.4 into the
corresponding acid chloride or into the free acid, with a compound
that introduces the radical of formula --CH.sub.2--COOR.sub.2
wherein R.sub.2 is as defined in claim 1.
3. A process according to claim 1, wherein the compound of formula
(2) is obtained by reacting a compound of formula 45with a compound
of formula CH.sub.3--CO--CH.sub.2--COOR.sub.2 and, optionally, then
with a compound that introduces a protecting group, to form a
compound of formula 46wherein R.sub.1 and R.sub.2 are as defined in
claim 1, and R.sub.8 and R.sub.9 are hydrogen or a protecting
group, introducing a double bond under acidic or basic conditions,
and removing any protecting group that may be present.
4. A process according to claim 1, wherein the compound of formula
(2) is obtained by reacting a compound of formula 47with a compound
of formula 48to form a compound of formula 49and reacting that
compound with a compound that introduces the radical of formula
--CH.sub.2--COOR.sub.2 wherein R.sub.1 and R.sub.2 are as defined
in claim 1, R.sub.6 and R.sub.7 are hydrogen or hydrocarbon
radicals, R.sub.11 is C.sub.1-C.sub.4alkyl or phenyl, especially
methyl or ethyl, Ph is phenyl and An.sup.- is an anion.
5. A process according to any one of claims 1 to 4, wherein there
is used as compound of formula (3) a compound of formula 50wherein
R.sub.1 and R.sub.2 are as defined in claim 1.
6. A process according to any one of claims 1 to 5, wherein the
compound of formula (4) is hydrolysed.
7. A process according to any one of claims 1 to 6, wherein R.sub.1
is isopropyl.
8. A process according to any one of claims 1 to 7, wherein
R.sub.2, R.sub.3, R.sub.4, R.sub.6 and R.sub.7 are
C.sub.1-C.sub.8alkyl.
9. A process according to any one of claims 1 to 8, wherein R.sub.5
is C.sub.1-C.sub.6alkyl or a radical of formula
--N(OR.sub.6)R.sub.7 in which R.sub.6 and R.sub.7 are
C.sub.1-C.sub.6alkyl.
10. A process according to any one of claims 3 and 5 to 8, wherein
R.sub.6 and R.sub.9 are each independently of the other hydrogen,
C.sub.1-C.sub.4alkylcarbonyl or C.sub.1-C.sub.4alkoxy-carbonyl.
11. A process according to any one of claims 2 and 6 to 9, wherein
Y is bromine.
12. A process according to any one of claims 1 to 11, wherein X is
a cation, especially sodium.
13. A compound of formula 51wherein R.sub.1 is C.sub.1-C.sub.6alkyl
and R.sub.2 is hydrogen or a hydrocarbon radical, especially
C.sub.1-C.sub.6alkyl.
14. A compound according to claim 13, wherein R.sub.1 is isopropyl
and R.sub.2 is C.sub.1-C.sub.6alkyl.
15. A process for the preparation of a compound of formula (2)
according to claim 13, wherein a compound of formula 52wherein
R.sub.1 is as defined in claim 13 and Y is bromine, chlorine,
iodine, --OSO.sub.2CF.sub.3 or --COCl, especially bromine, is
reacted with a compound that introduces the radical of formula
--CH.dbd.CH--Z, wherein Z is the radical --COOR.sub.4, --COR.sub.5
or --CN, R.sub.4 is hydrogen or a hydrocarbon radical and R.sub.5
is a hydrocarbon radical or unsubstituted or substituted amino, and
the resulting compound of formula 53optionally after conversion of
the compound of formula (6) wherein Z is the radical --COOR.sub.4
into the corresponding acid chloride or into the free acid, is
reacted with a compound that introduces the radical of formula
--CH.sub.2--COOR.sub.2 wherein R.sub.2 is as defined in claim
13.
16. A process for the preparation of a compound of formula (2)
according to claim 13, wherein a compound of formula 54is reacted
with a compound of formula CH.sub.3CO--CH.sub.2--COOR.sub.2 and,
optionally, then with a compound that introduces a protecting
group, to form the compound of formula 55wherein R.sub.1 and
R.sub.2 are as defined in claim 13 and R.sub.8 and R.sub.9 are
hydrogen or a protecting group, a double bond is introduced under
acidic or basic conditions, and any protecting group that may be
present is removed.
17. A process for the preparation of a compound of formula (2)
according to claim 13, wherein a compound of formula 56is reacted
with a compound of formula 57to form the compound of formula 58and
that compound is reacted with a compound that introduces the
radical of formula --CH.sub.2--COOR.sub.2 wherein R.sub.1 and
R.sub.2 are as defined in claim 13, R.sub.6 and R.sub.7 are
hydrogen or hydrocarbon radicals, R.sub.11, is C.sub.1-C.sub.4alkyl
or phenyl, especially methyl or ethyl, Ph is phenyl and An.sup.- is
an anion
18. The use of a compound of formula (2) according to claim 13 as
an intermediate in the preparation of a compound of formula (1)
according to claim 1.
19. A compound of formula 59wherein R.sub.1 is C.sub.1-C.sub.6alkyl
and R.sub.2 is hydrogen or a hydrocarbon radical, especially
C.sub.1-C.sub.6alkyl.
20. A compound according to claim 19 of formula 60wherein R.sub.1
and R.sub.2 are as defined in claim 19.
21. A compound according to either claim 19 or claim 20, wherein
R.sub.1 is isopropyl and R.sub.2 is C.sub.1-C.sub.6alkyl.
22. The use of a compound of formula (3) according to claim 19 as
an intermediate in the preparation of a compound of formula (1)
according to claim 1.
23. A compound of formula 61wherein R.sub.1 is
C.sub.1-C.sub.6alkyl, and R.sub.6 and R.sub.7 are hydrogen or
hydrocarbon radicals, especially C.sub.1-6alkyl.
24. A compound according to claim 23, wherein R.sub.1 is isopropyl
and R.sub.6 and R.sub.7 are C.sub.1-C.sub.6alkyl.
25. The use of a compound of formula (8) according to claim 23 as
an intermediate in the preparation of a compound of formula (1)
according to claim 1 or of a compound of formula (2) according to
claim 13.
26. A compound of formula 62wherein R.sub.1 is C.sub.1-C.sub.6alkyl
and Y is bromine, chlorine or iodine, especially bromine.
27. A compound according to claim 26, wherein R.sub.1 is isopropyl
and Y is bromine.
28. The use of a compound of formula (5) according to claim 26 as
an intermediate in the preparation of a compound of formula (1)
according to claim 1 or of a compound of formula (2) according to
claim 13.
Description
[0001] The present invention relates to a process for the
preparation of indole derivatives and to novel intermediates.
[0002] Indole derivatives of the formula (1) hereinbelow are known
as pharmaceutical active ingredients (e.g. from U.S. Pat. No.
4,739,073). Fluvastatin, an HMG-CoA reductase inhibitor, that is, a
cholesterol-biosynthesis inhibitor, is an important indole
derivative that is used in the treatment of hyperlipoproteinaemia
and arteriosclerosis.
[0003] Known processes for the preparation of the indole compounds
of formula (1) do not in all cases meet the demands made in terms
of yield and economy of the process.
[0004] It is accordingly the aim of the present Application to make
available a novel process for the preparation of indole compounds
of formula (1) by means of which such compounds can be obtained in
as high a yield as possible.
[0005] The present invention thus relates to a process for the
preparation of compounds of formula 5
[0006] wherein R.sub.1 is C.sub.1-C.sub.6alkyl and
[0007] X is hydrogen, a hydrocarbon radical or a cation,
[0008] in which process a compound of formula 6
[0009] wherein R.sub.1 is as defined above and R.sub.2 is hydrogen
or a hydrocarbon radical, is reduced, the resulting compound of
formula 7
[0010] wherein R.sub.1 and R.sub.2 are as defined above, is reacted
with a compound that introduces the radical of formula
CH.sub.2--COOR.sub.3 wherein R.sub.3 has the meanings given above
for R.sub.2, and the resulting compound of formula 8
[0011] is reduced and optionally hydrolysed.
[0012] There come into consideration as C.sub.1-C.sub.6alkyl
radicals for R.sub.1, for example, methyl, ethyl, n- or iso-propyl,
n-, iso-, sec- or tert-butyl, and straight-chain or branched pentyl
or hexyl. C.sub.1-4Alkyl radicals are preferred. R.sub.1 is
preferably propyl, especially isopropyl.
[0013] There come into consideration as hydrocarbon radicals for
R.sub.2, R.sub.3 and X, each independently of the others, for
example unsubstituted or substituted alkyl, alkenyl, alkynyl and
phenyl radicals. Special mention may be made of unsubstituted or
substituted C.sub.1-C.sub.12alkyl, C.sub.3-C.sub.12-alkenyl,
C.sub.3-C.sub.12alkynyl and phenyl radicals. Preferably, R.sub.2,
R.sub.3 and X are each independently of the others unsubstituted or
substituted alkyl radicals, especially C.sub.1-C.sub.12alkyl
radicals and preferably C.sub.1-C.sub.6alkyl radicals. There may be
mentioned as an example of substituents of the alkyl radicals, for
example, phenyl that is unsubstituted or further substituted on the
phenyl ring by nitro or by hydroxy. There may be mentioned as
examples of R.sub.2, R.sub.3 and X methyl, ethyl, n- or iso-propyl,
n-, iso-, sec- or tert-butyl, allyl, benzyl, nitrobenzyl and also
hydroxybenzyl. R.sub.2, R.sub.3 and X are especially preferably
C.sub.1-C.sub.4alkyl. R.sub.2 is more especially preferably methyl
or ethyl, especially methyl. R.sub.3 and X are more especially
preferably butyl, especially tert-butyl.
[0014] When the radical X is a cation, it may be, for example,
sodium or potassium, especially sodium.
[0015] The reduction of the compound of formula (2) to the compound
of formula (3) can be carried out according to commonly used
methods, such as are described, for example, in Houben-Weyl,
Methoden der organischen Chemie, Volume 7/2b, pages 1991 ff, Georg
Thieme Verlag, Stuttgart, 1976. The reduction can be effected, for
example, with a metal hydride, such as lithium aluminium hydride,
diisobutylaluminium hydride or, especially, sodium borohydride, in
an anhydrous, inert organic solvent, for example an ether, such as
tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or
1,2-diethoxyethane. When sodium borohydride is used, it is
preferable to use as solvent a mixture of such ethers with a lower
alcohol, especially methanol. There comes Into consideration as the
temperature for the reaction, for example, a range of from -80 to
25.degree. C. Preferably, the reaction is carried out in an inert
gas atmosphere.
[0016] The reaction of the compound of formula (3) to form the
compound of formula (4) can be carried out, for example, according
to the procedure described in U.S. Pat. No. 4,870,199. For example
a compound of formula CH.sub.3--COOR.sub.3, such as tert-butyl
acetate, may be used as the compound that introduces the radical of
formula --CH.sub.2--COOR.sub.3, R.sub.3 having the meanings and
preferred meanings mentioned above. The reaction is generally so
carried out that, in the presence of a strong base, such as lithium
diisopropylamide, a monoanion of the compound of formula
CH.sub.3--COOR.sub.3 is formed. The reaction is usually performed
in an anhydrous, inert organic solvent, for example an ether, such
as diethyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxyethane or,
especially, tetrahydrofuran, the reaction generally being carried
out in an inert gas atmosphere, at a temperature of from -80 to
25.degree. C. In a next step, the monoanion formed is reacted with
the compound of formula (3), that reaction usually being performed
in the same solvent and in an inert gas atmosphere, at a
temperature of, for example, from -80 to 25.degree. C.
[0017] The reduction of the compound of formula (4) can be carried
out, for example, by way of a cyclic boronate using sodium
borohydride, as in O. Tempkin, Tetrahedron, Vol. 53, No. 31,
10659-10670 (1997). The reduction is effected, for example, in an
ether and/or lower alcohol, such as tetrahydrofuran or methanol, at
a temperature of, for example, from -50 to -80.degree. C. As borane
there comes into consideration, for example, diethyl methoxyborane.
The reduction can alternatively be carried out with
diisobutylaluminium hydride or tributyltin hydride, as described in
S. Kiyooka, Tetrahedron Letters, Vol. 27, No. 26, 3009-3012 (1986),
or with zinc borohydride, as described in F. Kathawala, Helv. Chim.
Acta, Vol. 69, 803-805 (1986). The reduction can also be carried
out with NaBH.sub.4 in the presence of triethylboranes as
complexing agents, as described in U.S. Pat. No. 4,739,073.
[0018] The hydrolysis of the compound obtained after reduction of
the compound of formula (4) can be carried out, for example, by
conventional basic hydrolysis of the ester. For that purpose, the
compound obtained after reduction of the compound of formula (4) is
treated with approximately one mole of an inorganic base, such as
an alkali metal hydroxide, for example potassium hydroxide or,
especially, sodium hydroxide, in a mixture of water and a
water-miscible organic solvent, for example a lower alcohol or an
ether, such as methanol, ethanol or tetrahydrofuran, at a
temperature of, for example, from 0 to 80.degree. C. It is also
possible to proceed with slightly less than the stoichiometric
amount of base and then remove excess ester by means of extraction
with a water-immiscible organic solvent, for example tert-butyl
methyl ether; freeze-drying can then be carried out. In order to
form the free acid, the ester can also be hydrolysed in an acidic
medium, it being possible for such a hydrolysis to be carried out
according to procedures known per se. It is preferable, following
the reduction of the compound of formula (4), for hydrolysis,
preferably with sodium hydroxide, to be carried out.
[0019] The compounds of formula (2) are novel and can be obtained,
for example, according to the following processes:
[0020] According to a process variant a) for the preparation of
compounds of formula (2), a compound of formula 9
[0021] wherein R.sub.1 has the meanings and preferred meanings
given hereinbefore and Y is bromine, chlorine, iodine,
--OSO.sub.2CF.sub.3 or --COCl, especially bromine,
[0022] is reacted with a compound that introduces the radical of
formula --CH.dbd.CH--Z, wherein
[0023] Z is the radical --COOR.sub.4, --COR.sub.5 or --CN, R.sub.4
is hydrogen or a hydrocarbon radical and R.sub.5 is a hydrocarbon
radical or unsubstituted or substituted amino,
[0024] and the resulting compound of formula 10
[0025] optionally after conversion of the compound of formula (6)
wherein Z is the radical COOR.sub.4 into the corresponding acid
chloride or into the free acid,
[0026] is reacted with a compound that introduces the radical of
formula --CH.sub.2--COOR.sub.2.
[0027] When R.sub.4 and R.sub.5 are hydrocarbon radicals, the
meanings and preferred meanings for hydrocarbon radicals given
hereinbefore for R.sub.2 apply. For R.sub.5 as unsubstituted or
substituted amino there comes into consideration, for example,
amino substituted by C.sub.1-C.sub.12alkyl and/or by
C.sub.1-C.sub.12alkoxy. In that case there preferably comes into
consideration a radical of formula --N(OR.sub.6)R.sub.1 wherein
R.sub.6 and R.sub.7 are hydrogen or hydrocarbon radicals,
especially C.sub.1-C.sub.6alkyl and preferably methyl.
[0028] When R.sub.6 and R.sub.7 are hydrocarbon radicals, the
meanings and preferred meanings for hydrocarbon radicals given
hereinbefore for R.sub.2 apply.
[0029] Preferred as radicals Z are the radicals of formula
--COOR.sub.4 or --CO--N(OR.sub.6)R.sub.7 wherein R.sub.4, R.sub.6
and R.sub.7 have the meanings and preferred meanings given
hereinbefore.
[0030] The compounds of formulae 11
[0031] are therefore of particular importance as compounds of
formula (6).
[0032] The reaction of the compound of formula (5) to form the
compound of formula (6) can be carried out according to methods
known per se. The process can be carried out, for example, by the
so-called Heck reaction, in which especially aromatic iodine or
bromine compounds are reacted with olefins in the presence of
palladium catalysts. The methodology is described, for example, in
R. F. Heck, Acc. Chem. Res. 1979, 12, 146; R. F. Heck, Org. React.
1982, 27, 345; and in R. F. Heck, Palladium Reactions in Synthesis,
Academic Press, London 1985, S. Brase and A. De Meijere in
Metal-catalyzed Cross-coupling Reactions, Chapter 3, Wiley--VCH,
DE-Weinheim 1998 and in WO-A-99/47474.
[0033] There come into consideration as palladium catalysts
especially those described under the general formula (VIIa) in
WO-A-99/47474, preferably the catalysts denoted K1 to K 11 in the
examples documented in that specification, it being possible for
the catalysts to be used especially in the amounts indicated
therein.
[0034] As compounds that introduce the radical of formula
--CH.dbd.CH--Z wherein Z is --COOR.sub.4 there come into
consideration, for example, those of formula
CH.sub.2=CH--COOR.sub.4, for example acrylic acid. As compounds
that introduce the radical of formula --CH.dbd.CH-Z wherein Z is
--CO--N(OR.sub.6)R.sub.7 there come into consideration, for
example, those of formula CH.dbd.CH--CO--N(OR.sub.6)R.sub.7, for
example N-methoxy-N-methylacrylamide. Mention may also be made of
the compound of formula CH.sub.2=CH--CN as compound that introduces
the radical of formula --CH.dbd.CH--Z.
[0035] The molar ratio of the reaction partners (compound of
formula (5)/compound introducing the radical of formula
--CH.dbd.CH--Z) of such coupling reactions is generally in the
range from 1:1 to 1:10, with preference being given to a ratio in
the range from 1:1 to 1:2. The reaction is carried out with cooling
up to the boiling temperature of the solvent, especially at from
room temperature up to the boiling temperature of the solvent
(reflux conditions). Suitable solvents are customary, especially
higher-boiling, solvents, for example non-polar aprotic solvents,
e.g. xylene or toluene, or polar aprotic solvents, e.g.
dimethylformamide, dimethoxyethane or dimethylacetamide. The
reaction product (6) obtainable can be worked up and isolated in a
manner known per se by means of customary purification methods, for
example by removal of the solvent and subsequent separation
procedures, for example fine distillation, recrystallisation,
preparative thin-layer chromatography, column chromatography or
preparative gas chromatography.
[0036] When, in the resulting compound of formula (6), Z is the
radical --COOR.sub.4 and R.sub.4 is a hydrocarbon radical, that
compound can subsequently be converted into the free acid by acid
hydrolysis of the ester. If desired, that compound can be converted
into the acid chloride before being further reacted. Both the acid
hydrolysis and the conversion into the acid chloride can be
effected in conventional manner according to known procedures.
[0037] The reaction of the compound of formula (6), especially the
compound of formula (7), with a compound that introduces the
radical of formula --CH.sub.2--COOR.sub.2 can be carried out, for
example, as described in A. Nudelman, Synthesis, No. 4, 568-570
(1999). The conversion of the compound of formula (6) into the acid
chloride and the reaction with a compound that introduces the
radical of formula --CH.sub.2--COOR.sub.2 can be carried out, for
example, as in W. Wierenga, J. Org. Chem., Vol. 44, No. 2, 310-311
(1979). As compounds that introduce the radical of formula
--CH.sub.2--COOR.sub.2 there may be mentioned, for example,
compounds of the formula HOOC--CH.sub.2--COOR.sub- .2, such as
monomethyl malonate or monoethyl malonate, such compounds being
understood as including also salts thereof, for example the
potassium salt.
[0038] The reaction of the compound of formula (6), especially of
the compound of formula (8), with a compound that introduces the
radical of formula --CH.sub.2--COOR.sub.2 can be carried out, for
example, analogously to the process described above for the
reaction of the compound of formula (3) to form the compound of
formula (4). As compounds that introduce the radical of formula
--CH.sub.2--COOR.sub.2 there may be mentioned in that connection,
for example, compounds of the formula CH.sub.3--COOR.sub.2, such as
ethyl acetate. A typical reaction by means of a Claisen reaction is
described in J. A. Turner, J. Org. Chem., Vol. 54, 4229-4231
(1989).
[0039] The compound of formula (5) can be obtained, for example, by
halogenating a corresponding compound in which Y is hydrogen. The
halogenation can be carried out according to generally known
methods. For the bromination, reference is made, for example, to
Houben-Weyl, Methoden der organischen Chemie, Volume 5/4, pages 233
ff, Georg Thieme Verlag, Stuttgart, 1960. There come into
consideration for the bromination, for example, elemental bromine,
N-bromosuccinimide, pyridinium bromide perbromide or
triphenylphosphine dibromide, in an inert, preferably halogenated
solvent, such as carbon tetrachloride, chloroform, chlorobenzene or
dichlorobenzene. The bromination is generally carried out at a
temperature of from -5 to 25.degree. C., and in the case of
N-bromosuccinimide at approximately from 40 to 85.degree. C.
[0040] The starting compounds wherein Y is hydrogen are known or
can be obtained analogously to known procedures, for example the
procedures indicated in U.S. Pat. No. 4,739,073.
[0041] According to a further process variant b) for the
preparation of compounds of formula (2), a compound of formula
12
[0042] is reacted with a compound of formula
CH.sub.3--CO--CH.sub.2--COOR.- sub.2 and, optionally, then with a
compound that introduces a protecting group, to form a compound of
formula 13
[0043] wherein R.sub.1 and R.sub.2 have the meanings and preferred
meanings indicated hereinbefore and R.sub.8 and R.sub.9 are
hydrogen or a protecting group,
[0044] a double bond is introduced under acidic or basic
conditions, and any protecting group that may be present is
removed.
[0045] As compounds that introduce a protecting group it is
possible to use the compounds customary for that purpose, such as,
for example, compounds that form readily removable esters or
carbonates. Examples include acid anhydrides of formula
(R.sub.10--CO).sub.2O and acid chlorides of formula
R.sub.10--CO--Cl, wherein R.sub.10 is C.sub.1-C.sub.4alkyl or
C.sub.1-C.sub.4alkoxy.
[0046] R.sub.6 and R.sub.9 are preferably each independently of the
other hydrogen, C.sub.1-C.sub.4alkylcarbonyl or
C.sub.1-C.sub.4alkoxycarbonyl, especially hydrogen, acetyl or
ethoxycarbonyl.
[0047] The reaction of a compound of formula (9) with a compound of
formula CH.sub.3--CO--CH.sub.2--COOR.sub.2 is effected, for
example, by formation of the dianion of the latter compound by
means of a strong base, and reaction of the dianion with a compound
of formula (9). There come into consideration as strong bases, for
example, n-butyllithium, lithium diisopropylamide and sodium
hydride. Sodium hydride forms only the monoanion, with the result
that, when it is used, a further base, such as n-butyllithium or
lithium diisopropylamide, is used for the formation of the dianion
from the monoanion. The reactions as a whole can be carried out at
a temperature of from -80 to 25.degree. C. in an anhydrous, inert
organic solvent, such as tetrahydrofuran, diethyl ether or
1,2-dimethoxyethane, in an inert gas atmosphere. The compound so
obtained can be intercepted using a readily removable protecting
group and then the double bond can be introduced under acidic or
basic conditions in an inert solvent, such as tetrahydrofuran,
diethyl ether, 1,2-dimethoxyethane or toluene. The protected enol
can then be hydrolysed likewise under basic or acidic conditions.
It is also possible to hydrolyse the intermediate dianion and
eliminate the alcohol under acidic conditions.
[0048] According to a further process variant c) for the
preparation of compounds of formula (2), a compound of formula
14
[0049] is reacted with a compound of formula 15
[0050] to form a compound of formula 16
[0051] and that compound is reacted with a compound that introduces
the radical of formula --CH.sub.2--COOR.sub.2 wherein R.sub.1 and
R.sub.2 have the meanings and preferred meanings given
herein-before, R.sub.6 and R.sub.7 are hydrogen or hydrocarbon
radicals, R.sub.11, is C.sub.1-C.sub.4alkyl or phenyl, especially
methyl or ethyl, preferably ethyl, Ph is phenyl and An.sup.- is an
anion.
[0052] R.sub.6 and R.sub.7 have the meanings and preferred meanings
indicated hereinbefore. R.sub.6 and R.sub.7 are preferably
C.sub.1-C.sub.6alkyl, especially methyl or ethyl, preferably
methyl.
[0053] In the compound of formula (11 b), there comes into
consideration as anion especially halogen, such as bromine or
preferably chlorine.
[0054] The reaction of the compound of formula (9) with a compound
of formula (11a) or (11b) is generally carried out in the presence
of a base, such as n-butyllithium or especially sodium hydride, in
an organic solvent, such as an ether, for example diethyl ether or
tetrahydrofuran, at a temperature of, for example, from -10 to
30.degree. C. Corresponding reactions are described in J. Boutagy,
Chemical Reviews, Vol. 74, No. 1, 87-99 (1974).
[0055] It is preferable in this process variant to carry out the
reaction of a compound of formula (9) with a compound of formula
(11a).
[0056] The reaction of the compound of formula (8) to form the
compound of formula (2) can be carried out as described
hereinabove.
[0057] For the preparation of compounds of formula (2), preference
is given to process variants a) and b), especially process variant
a).
[0058] The compounds of formula (3) may be obtained in the form of
a racemate or in the form of enantiomerically pure compounds of
formula (3a) in the following (R) configuration 17
[0059] or especially in the form of enantiomerically pure compounds
of formula (3b) in the following (S) configuration 18
[0060] The racemate can be resolved into the optically pure
antipodes by means of known methods for the separation of
enantiomers, for example by means of preparative chromatography
using chiral supports (HPLC) or by esterification and
crystallisation out using optically pure precipitating agents, for
example D-(-) or L-(-)-mandelic acid or (+)- or
(-)-10-camphor-sulfonic acid.
[0061] Enantiomerically pure or stereoisomerically pure compounds
are to be understood here and hereinafter as compounds that are in
at least 60%, especially 80% and, preferably, 90% pure form.
Especially preferably they are in at least 95%, preferably 97.5%
and, especially, 99% enantiomerically pure or stereoisomerically
pure form.
[0062] The compounds of formula (1) may be obtained in the form of
a mixture of stereoisomers or in pure form, especially in the
following (3R,5S) configuration: 19
[0063] Further stereoisomers that may be mentioned are those of the
corresponding (3R,5R), (3S,5S) and (3S,5R) configurations.
[0064] Stereoisomerically pure compounds of formula (1), such as
those of formula (1a), can be obtained according to procedures
known for that purpose. Racemate cleavage can be carried out as
indicated above under formulae (3a) and (3b).
[0065] The present invention relates also to the novel compounds of
formulae (2), (3), (5) and (8), to processes for the preparation
thereof, and also to the use of compounds of formula (2), (3), (5)
or (8) as intermediates in the preparation of compounds of formula
(1). The present invention relates also to the use of compounds of
formula (5) or (8) as intermediates in the preparation of compounds
of formula (2).
[0066] The preferred meanings mentioned hereinabove apply to the
novel compounds of formulae (2), (3), (5) and (8).
[0067] As process for the preparation of compounds of formula (2)
there comes into consideration, for example, the preparation
according to process variant a), b) or c), especially according to
process variant a) or b), preferably according to process variant
a).
[0068] As process for the preparation of compounds of formula (3)
there comes into consideration, for example, the reduction of the
compound of formula (2). Preferably, the preparation of the
compound of formula (2) is in that case carried out according to
process variant a), b) or c), especially according to process
variant a) or b), preferably according to process variant a).
[0069] As process for the preparation of compounds of formula (5)
there comes into consideration, for example, the above-described
halogenation, especially brominabon, of the corresponding compound
wherein Y is hydrogen.
[0070] As process for the preparation of compounds of formula (8)
there comes into consideration especially the reaction of a
compound of formula (5) with a compound that introduces the radical
of formula --CH.dbd.CH--CO--N(OR.sub.6)R.sub.7 or the reaction of a
compound of formula (9) with a compound of formula (11a) or (11b),
preference being given to the first-mentioned reaction.
[0071] The following Examples illustrate the invention:
EXAMPLE 1
[0072] 3-4-Fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde
20
[0073] 5.77 g (78.96 mmol) of DMF are weighed into a 100 ml
three-necked round-bottomed flask, equipped with a magnetic
stirrer, thermometer, dropping funnel, reflux condenser and
nitrogen delivery line, and cooled, with stirring, to 3.degree. C.
12.11 g (78.96 mmol) of phosphorus oxychloride are then slowly
added dropwise so that the internal temperature does not exceed
10.degree. C. The reaction mixture is then heated to 80.degree. C.
and 10 g (39.48 mmol) of 3-(4-fluorophenyl)-1-iso-
propyl-1H-indole, dissolved in 10 ml of DMF, are added dropwise in
the course of 30 min. Stirring is subsequently carried out for 1.5
hours at that temperature. Cooling and dilution with 10 ml of DMF
are then carried out. The reaction mixture is transferred into a
dropping funnel and, with stirring, slowly added dropwise at
40.degree. C. to 10 g (0.25 mol) of sodium hydroxide in 200 ml of
water. The aqueous phase is extracted four times with 50 ml of
toluene and the combined organic phases are washed six times with
100 ml of water. Subsequently, 10 g of silica gel are added, the
mixture is stirred for 1 hour and filtration is carried out,
followed by washing three times with 50 ml of toluene and
concentration by evaporation. 10.17 g of a brown oil are obtained,
which is dissolved in 100 ml of hexane under reflux. 10 g of silica
gel are added, and filtration is carried out while hot, followed by
washing three times with 50 ml of hot hexane. The filtrate is
concentrated by evaporation and the residue is recrystallised from
94% ethanol. Slightly beige crystals having a melting point of from
89.5 to 91.degree. C. are obtained.
EXAMPLE 2
[0074]
5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylhex-2-enoi-
c acid methyl ester 21
[0075] 3.85 g (88.16 mmol) of sodium hydride (55%) are introduced
into a thoroughly heated, 500 ml three-necked round-bottomed flask,
equipped with a thermometer, dropping funnel, septum, nitrogen
delivery line and magnetic stirrer, and washed twice with 25 ml of
pentane. The pentane is removed using a pipette and the sodium
hydride is blown dry with nitrogen. 100 ml of THF, rendered
absolute using sodium, are then added, and the suspension is cooled
to 5.degree. C. by means of an ice bath with stirring. 10.24 g
(88.16 mmol) of methyl aceto-acetate dissolved in 50 ml of absolute
THF are then slowly added dropwise so that the internal temperature
does not exceed 10.degree. C. The suspension is stirred for 30 min.
while cooling with ice. 56.3 ml (90.12 mmol) of butyllithium (1.6M
in hexane) are slowly added dropwise to the almost clear solution
so that the internal temperature does not exceed 10.degree. C. The
clear yellow solution is stirred for 20 min. while cooling with
ice. 15.0 g (53.32 mmol) of
3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved
in 100 ml of absolute THF are added dropwise over a period of 5
min., in the course of which the internal temperature rises to
10.degree. C. After 45 min., a thick yellow suspension has formed
to which 54.4 g (533.2 mmol) of acetic anhydride are added dropwise
so that the internal temperature does not exceed 10.degree. C. The
slightly turbid, yellow solution is stirred for 15 min. and then
warmed to room temperature. The reaction mixture is poured into 250
ml of 1 N hydrochloric acid and extracted 3 times with ethyl
acetate. The combined organic phases are washed twice with 50 ml of
saturated sodium chloride solution, once with 100 ml of 5% sodium
hydrogen carbonate solution and three times with saturated sodium
chloride solution in order to render neutral, dried over magnesium
sulfate, filtered and concentrated by evaporation at 80.degree. C.
An orange oil is obtained which, according to NMR, also contains
already eliminated product
((E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indo-
l-2-yl]-3-methylpenta-2,4-dienoic acid methyl ester).
EXAMPLE 3
[0076]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-methylpenta--
2,4-dienoic acid methyl ester 22
[0077] 2.0 g of crude
5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-m-
ethylhex-2-enoic acid methyl ester in 50 ml of toluene are
introduced into a 100 ml three-necked round-bottomed flask,
equipped with a magnetic stirrer, thermometer, reflux condenser and
nitrogen delivery line, 0.9 g (8.87 mmol) of triethylamine are
added and the yellow solution is heated at reflux with stirring.
After 2 hours, the reaction mixture is cooled, diluted with 50 ml
of toluene, washed once with 100 ml of 1N hydrochloric acid and
three times with 50 ml of water and concentrated by evaporation
using a rotary evaporator. The crude product (orange oil) is
purified by means of flash chromatography (hexane/ethyl
acetate=10:1). An orange resin is obtained which, according to NMR,
contains approximately 30%
(E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-enoic
acid methyl ester (mixture of keto and enol forms).
EXAMPLE 4
[0078]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-en-
oic acid methyl ester 23
[0079] 0.63 g (1.49 mmol) of
(E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indo-
l-2-yl]-3-methylpenta-2,4-dienoic acid methyl ester in 20 ml of THF
are introduced into a 50 ml round-bottomed flask equipped with a
magnetic stirrer and nitrogen delivery line, 4 ml of 1 N ammonium
hydroxide solution are added, and the mixture is stirred for 6
hours at room temperature. The reaction mixture is poured into 200
ml of saturated sodium chloride solution and extracted twice with
100 ml of ethyl acetate, and the organic phase is washed three
times with 50 ml of water, dried over magnesium sulfate, filtered
and concentrated by evaporation. The crude product is purified by
means of flash chromatography (hexane/ethyl acetate=9:1). An orange
resin is obtained which, according to NMR, is the product in a
keto-enol equilibrium of approximately 3:1.
EXAMPLE 5
[0080]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-en-
oic acid methyl ester 24
[0081] In a 2 litre round-bottomed flask equipped with a magnetic
stirrer and nitrogen delivery line, 30.5 g of crude
5-[3-(4-fluorophenyl)-1-isopr-
opyl-1H-indol-2-yl]-3-methylhex-2-enoic acid methyl ester are
dissolved in 250 ml of THF, 13.49 g (133.3 mmol) of triethylamine
are added and the yellow solution is heated under reflux for 2
hours. The reaction mixture is then cooled to room temperature, 53
ml (212 mmol) of 4N ammonium hydroxide solution are added and the
mixture is stirred vigorously for 3 hours. The reaction mixture is
then poured into 1 litre of saturated sodium chloride solution and
extracted three times with 250 ml of ethyl acetate. The combined
organic phases are washed once with 100 ml of 1 N hydro-chloric
acid and three times with saturated sodium chloride solution, dried
over magnesium sulfate, filtered and concentrated by evaporation.
The crude product (22.78 g of an orange resin) is purified by means
of flash chromatography (hexane/ethyl acetate=9:1). A resin is
obtained which, according to NMR, is the product in a keto-enol
equilibrium of approximately 3:1.
EXAMPLE 6:
[0082]
5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxypent--
2-enoic acid methyl ester 25
[0083] 0.256 g (5.87 mmol) of sodium hydride (55%) is introduced
into a thoroughly heated 100 ml three-necked round-bottomed flask,
equipped with a magnetic stirrer, thermometer, dropping funnel and
nitrogen delivery line, and washed twice with 5 ml of pentane. The
pentane is removed using a pipette and the sodium hydride is blown
dry with nitrogen. 20 ml of THF, rendered absolute using sodium,
are then added, and the suspension is cooled to 3.degree. C. by
means of an ice bath with stirring. 0.68 g (5.87 mmol) of methyl
acetoacetate dissolved in ml of absolute THF is then slowly added
dropwise so that the internal temperature does not exceed 5.degree.
C. The suspension is stirred for 15 min. while cooling with ice.
3.75 ml (6.0 mmol) of butyllithium (1.6M in hexane) are slowly
added dropwise to the almost clear solution so that the internal
temperature does not exceed 5.degree. C. The clear yellow solution
is stirred for 20 min. while cooling with ice. 1.0 g (3.55 mmol) of
3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde dissolved
in 5 ml of absolute THF are added dropwise over a period of 2 min.,
in the course of which the internal temperature rises to 10.degree.
C. After 4 hours, the reaction mixture is poured into 100 ml of
ice-water, stirred for 10 min. and extracted 3 times with 100 ml of
ethyl acetate. The combined organic phases are washed twice with
100 ml of saturated sodium chloride solution in order to render
neutral, dried over magnesium sulfate, filtered and concentrated by
evaporation at 80.degree. C.
[0084] An orange resin is obtained, which is in the enol form
according to NMR and which is used further without being
purified.
EXAMPLE 7
[0085]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-en-
oic acid methyl ester 26
[0086] 1 g of crude
5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-d-
ihydroxypent-2-enoic acid methyl ester in 50 ml of toluene are
introduced into a 100 ml three-necked round-bottomed flask equipped
with a magnetic stirrer, thermometer, reflux condenser and nitrogen
delivery line, 48 mg (0.025 mmol) of toluene-4-sulfonic acid are
added and the mixture is stirred for 4 hours under reflux. The
mixture is then cooled to room temperature, washed once with 25 ml
of saturated sodium hydrogen carbonate solution and twice with 50
ml of saturated sodium chloride solution, dried over magnesium
sulfate, filtered and concentrated by evaporation. The crude
product is purified by means of flash chromatography (hexane/ethyl
acetate=9:1). An orange resin is obtained which, according to NMR,
is the product in a keto-enol equilibrium of approximately 3:1.
EXAMPLE 8
[0087]
3,5-Bis-ethoxycarbonyloxy-5-[3-(4-fluorophenyl)-1-isopropyl-1H-indo-
l-2-yl]-pent-2-enoic acid methyl ester 27
[0088] 0.256 g (5.87 mmol) of sodium hydride (55%) are introduced
into a thoroughly heated 100 ml three-necked round-bottomed flask,
equipped with a magnetic stirrer, thermometer, dropping funnel and
nitrogen delivery line, and washed twice with 5 ml of pentane. The
pentane is removed using a pipette and the sodium hydride is blown
dry with nitrogen. 20 ml of THF, rendered absolute using sodium,
are then added, and the suspension is cooled to 3.degree. C. by
means of an ice bath with stirring. 0.68 g (5.87 mmol) of methyl
acetoacetate dissolved in 5 ml of absolute THF are then slowly
added dropwise so that the internal temperature does not exceed
5.degree. C. The suspension is stirred for 15 min. while cooling
with ice. 3.75 ml (6.0 mmol) of butyllithium (1.6M in hexane) are
slowly added dropwise to the almost clear solution so that the
internal temperature does not exceed 5.degree. C. The clear yellow
solution is stirred for 20 min. while cooling with ice. 1.0 g (3.55
mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole-2-carbaldehyde
dissolved in 10 ml of absolute THF are added dropwise over a period
of 2 min., in the course of which the internal temperature rises to
10.degree. C. After 1.5 hours, the reaction mixture is cooled to
-10.degree. C., 5.39 g (49.7 mmol) of ethyl chloroformate are added
dropwise and stirring is carried out for 30 min. at -10.degree. C.
Heating to room temperature is then carried out, 15 ml of water, 10
ml of 2N hydrochloric acid and 25 ml of acetone are added and
stirring is carried out for 1 hour. The phases are separated, the
aqueous phase is extracted three times with 50 ml of ethyl acetate
and the combined organic phases are washed once with 50 ml of
saturated sodium hydrogen carbonate solution and three times with
50 ml of saturated sodium chloride solution, dried over magnesium
sulfate, filtered and concentrated by evaporation. An orange resin
is obtained, which is virtually pure according to NMR and which is
used further without being purified.
EXAMPLE 9
[0089]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-en-
oic acid methyl ester 28
[0090] In a 100 ml three-necked, round-bottomed flask, equipped
with a magnetic stirrer, thermometer, reflux condenser and nitrogen
delivery line, 2.17 g of crude
3,5-bis-ethoxy-carbonyloxy-5-[3-(4-fluorophenyl)-1--
isopropyl-1H-indol-2-yl]-pent-2-enoic acid methyl ester are
dissolved in 50 ml of DMF, 1.0 g of pyridinium p-toluenesulfonate
is added and stirring is carried out for 4 hours at 80.degree. C.
The reaction mixture is then cooled, poured into 150 ml of
saturated sodium chloride solution and extracted four times with 50
ml of ethyl acetate. The combined organic phases are washed six
times with 50 ml of water, dried over magnesium sulfate, filtered
and concentrated by evaporation. The crude product (brownish-orange
resin) is purified by means of flash chromatography (hexane/ethyl
acetate=10:1). An orange resin is obtained which, according to NMR,
is the product in a keto-enol equilibrium of approximately 3:1.
EXAMPLE 10
[0091] 2-Bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole 29
[0092] 20 g (78.95 mmol) of
3-(4-fluorophenyl)-1-isopropyl-1H-indole, 200 ml of THF and 200 ml
of chlorobenzene are introduced into a 1.5 litre sulfonating flask,
equipped with an anchor stirrer, thermometer and nitrogen delivery
line, and cooled to 3.degree. C. with stirring. 26.58 g (78.95
mmol) of pyridinium bromide perbromide are then added and stirring
is carried out for 1.25 hours at 3.degree. C. 680 g of a 5% sodium
hydrogen carbonate solution are then added dropwise in the course
of 10 min. The phases are separated and the aqueous phase is
extracted three times with 150 ml of chlorobenzene. The combined
organic phases are washed twice with 340 ml of 5% sodium hydrogen
carbonate solution and twice with 220 ml of water, dried over
magnesium sulfate, filtered and concentrated by evaporation. The
brown residue is dissolved in 125 ml of methylene chloride, 125 ml
of 94% ethanol are added and the methylene chloride is distilled
off at normal pressure. The solution is cooled slowly to room
temperature and then to 3.degree. C., and the precipitate is
filtered off, washed three times with 10 ml of ice-cold 94% ethanol
and dried overnight at RT/125 T. Beige crystals having a melting
point of from 110 to 111.5.degree. C. are obtained. Elemental
analysis: Found 4.95% H; 61.23% C; 4.04% N; 22.9% Br; 5.67% F.
Theory 4.55% H; 61.46% C; 4.22% N; 24.05% Br; 5.72% F.
EXAMPLE 11
[0093]
(E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-me-
thylacrylamide 30
[0094] 2 g (6.02 mmol) of
2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole and 10 ml of DMF
are introduced into a 50 ml three-necked round-bottomed flask,
which has been purged with nitrogen and is equipped with a magnetic
stirrer, thermometer, reflux condenser, gas inlet tube and nitrogen
delivery line, and degassing is carried out for 45 min. by
introducing nitrogen. 24 mg (1.0 mol %) of the catalyst K4 from
WO-A-99/47474 and 0.539 g (6.59 mmol) of sodium acetate are then
added and degassing is carried out for a further 15 min. 1.08 g
(8.43 mmol) of N-methoxy-N-methylacrylamide (prepared analogously
to a procedure of S. Nahm, Tetrahedron Letters 22, 3815 (1981)) are
subsequently added and the suspension is heated at reflux for 1.75
hours. A further 0.5 g (4.34 mmol) of N-methoxy-N-methylacrylamide
is added and refluxing is carried out for 1.5 hours. Cooling is
then carried out followed by dilution with 50 ml of water and
extraction three times with 50 ml of ethyl acetate. The combined
organic phases are washed three times with 50 ml of water, dried
over magnesium sulfate, filtered and concentrated by evaporation.
Purification by means of flash chromatography (hexane/ethyl
acetate=2:1) yields a yellow solid that is pure according to NMR.
Recrystallisation from 94% ethanol yields slightly yellow crystals
having a melting point of from 123 to 124.degree. C.
EXAMPLE 12
[0095]
(E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-methoxy-N-me-
thylacrylamide 31
[0096] 0.465 g (10.65 mmol) of sodium hydride (55%) are introduced
into a 100 ml three-necked, round-bottomed flask, equipped with a
magnetic stirrer, thermometer, dropping funnel and nitrogen
delivery line, and washed twice with 5 ml of pentane. The pentane
is removed using a pipette and the sodium hydride is blown dry with
nitrogen. 10 ml of THF, rendered absolute using sodium, are added,
and 1.84 g (7.46 mmol) of diethyl
(N-methoxy-N-methylcarbamoyl-methyl)phosphonate dissolved in 5 ml
of THF are slowly added dropwise so that the temperature does not
exceed 30.degree. C. 1 g (3.55 mmol) of
3-(4-fluorophenyl)-1-isopropyl-1H-indole- -2-carbaldehyde dissolved
in 10 ml of THF is then added dropwise and the clear, slightly
yellow solution is stirred overnight. The reaction mixture is
poured into 100 ml of water and extracted 3 times with 50 ml of
ethyl acetate. The combined organic phases are washed twice with 50
ml of saturated sodium chloride solution, dried over magnesium
sulfate, filtered and concentrated by evaporation. Flash
chromatography (hexane/ethyl acetate=2:1) and crystallisation from
94% ethanol yields slightly yellow crystals having a melting point
of from 123 to 124.degree. C.
EXAMPLE 13
[0097]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-en-
oic acid ethyl ester 32
[0098] 1.85 ml (12.97 mmol) of diisopropylamine, dried over KOH, in
6 ml of THF, rendered absolute using sodium, are introduced into a
thoroughly heated 50 ml three-necked round-bottomed flask, equipped
with a magnetic stirrer, thermometer and nitrogen delivery line,
and cooled to -50.degree. C. using an ethanol/dry-ice bath. 8.1 ml
(12.97 mmol) of butyllithium (1.6M in hexane) are slowly added
dropwise so that the internal temperature does not exceed
-40.degree. C. Heating to from -5 to 0.degree. C. is carried out
slowly, followed by stirring at that temperature for 30 min.
Cooling to -65.degree. C. is then carried out and 1.30 ml (12.94
mmol) of ethyl acetate are slowly added dropwise so that the
internal temperature does not exceed -60.degree. C. Stirring is
subsequently carried out for 40 min. at -65.degree. C. and then
1.20 g (3.28 mmol) of
(E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-N-met-
hoxy-N-methylacrylamide, dissolved in 5 ml of THF, are added
dropwise in the course of 25 min. and stirring is carried out for
one hour at that temperature. The temperature is then increased to
-5.degree. C. in the course of 15 min. and stirring is carried out
for 45 min. 8 ml of saturated ammonium chloride solution are added
dropwise over a period of 3 min., in the course of which the
temperature rises to 12.degree. C. Stirring is then carried out for
15 min., 10 ml of toluene are added, the phases are separated and
the aqueous phase is extracted three times with 20 ml of toluene.
The combined organic phases are washed with saturated sodium
chloride solution until neutral, dried over magnesium sulfate,
filtered and concentrated by evaporation. Purification of the crude
product by means of flash chromatography (hexane/ethyl acetate=9:1)
yields a viscous orange resin which, according to NMR, is the
product in a keto-enol equilibrium of approximately 3:1.
EXAMPLE 14
[0099] (E)-3-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-acrylic
acid 33
[0100] 2 g (6.02 mmol) of
2-bromo-3-(4-fluorophenyl)-1-isopropyl-1H-indole- , 10 ml of DMF
and 0.5 ml of water are introduced into a 50 ml three-necked,
round-bottomed flask, which has been purged with nitrogen and is
equipped with a magnetic stirrer, thermometer, reflux condenser,
gas inlet tube and nitrogen delivery line, and degassing is carried
out for 30 min. by introducing nitrogen. 24 mg (1.0 mol %) of the
catalyst K4 from WO-A-99/47474 and 2.15 g (6.6 mmol) of caesium
carbonate are then added and degassing is carried out for a further
1 hour. 1.0 g (13.8 mmol) of acrylic acid are subsequently added
and the suspension is heated at reflux for 2 hours. The DMF is then
distilled off, the residue is cooled, 10 ml of 1 N hydrochloric
acid are added and the aqueous phase is extracted three times with
50 ml of ethyl acetate. The combined organic phases are washed
three times with 30 ml of saturated sodium carbonate solution,
slightly acidified again using 1 N hydrochloric acid, and washed
three times with 50 ml of saturated sodium chloride solution in
order to render neutral. Drying over magnesium sulfate, filtration
and concentration by evaporation are then carried out. The residue
(1.83 g) is dissolved in THF, 5 g of silica gel are added and the
solution is concentrated by evaporation using a rotary evaporator.
The charged silica gel is transferred into a glass frit, and
non-polar secondary products are eluted using hexanelethyl
acetate=10:1 and then the product is eluted using ethyl acetate.
Concentration by evaporation yields a yellow solid which, according
to NMR, is the desired product in pure form.
EXAMPLE 15
[0101]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-oxopent-4-en-
oic acid methyl ester 34
[0102] 0.8 g (2.46 mmol) of
(E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol- -2-yl]-acrylic acid
in 4 ml of THF are introduced into a 50 ml three-necked
round-bottomed flask equipped with a magnetic stirrer, thermometer,
reflux condenser and nitrogen delivery line. 0.5 g (2.96 mmol) of
1,1-carbonyldiimidazole is then added in portions in the course of
5 min. and stirring is carried out at room temperature for 1 hour.
0.24 g (2.46 mmol) of magnesium chloride and 0.39 g (2.46 mmol) of
monomethyl malonate potassium salt are then added and the
suspension is stirred for 24 hours at 35.degree. C. The reaction
mixture is cooled and filtered and the residue is washed twice with
25 ml of THF. The filtrate is concentrated by evaporation, taken up
in 30 ml of ethyl acetate, washed with 15 ml of 1N hydrochloric
acid, three times with 20 ml of saturated sodium hydrogen carbonate
solution and three times with saturated sodium chloride solution,
dried over magnesium sulfate, filtered and concentrated by
evaporation. The residue is purified by means of flash
chromatography (hexane/ethyl acetate=8:1). An orange resin is
obtained which, according to NMR, is the product in a keto-enol
equilibrium of approximately 3:1.
EXAMPLE 16
[0103]
(E)-5-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3-hydroxypent--
4-enoic acid methyl ester 35
[0104] 15.39 g (40.56 mmol) of
(E)-5-[3-(4-fluorophenyl)-1-isopropyl-1H-in-
dol-2-yl]-3-oxopent-4-enoic acid methyl ester in 300 ml of
THF/methanol=1:1 are introduced into a 500 ml three-necked
round-bottomed flask, equipped with a magnetic stirrer, thermometer
and nitrogen delivery line, and cooled to -65.degree. C. by means
of an acetone/dry-ice bath. 1.84 g (48.67 mmol) of sodium
borohydride are added and the solution is stirred for 1.25 hours at
-65.degree. C. The cooling means is then removed, the reaction
mixture is heated to 0.degree. C. in the course of 35 min. and is
then stirred at that temperature for 35 min. The reaction mixture
is poured into 24 g (0.39 mol) of acetic acid in 1.5 litres of
water and extracted three times with 500 ml of ethyl acetate. The
combined organic phases are washed three times with 300 ml of
water, dried over magnesium sulfate, filtered and concentrated by
evaporation. Purification by means of flash chromatography
(hexane/ethyl acetate=3:1) yields an orange resin having an R.sub.1
value of 0.23 (hexane/ethyl acetate=3:1). According to NMR the
product is in pure form.
[0105] The enantiomers can be resolved by means of HPLC on a
Chiracel AD column using n-hexane/ethanol=99:1 at a flow rate of 1
ml/min., the retention times being 25.29 and 28.02 min.
EXAMPLE 17
[0106]
(E)-7-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-ox-
ohept-6-enoic acid tert-butyl ester 36
[0107] 11.41 (112.72 mmol) of diisopropylamine (dried over KOH) are
weighed into a thoroughly heated 500 ml three-necked round-bottomed
flask, equipped with a magnetic stirrer, thermometer, dropping
funnel, nitrogen delivery line and ethanl/dry-ice bath, and 50 ml
of THF (dried over sodium) are added. Under a nitrogen atmosphere,
cooling to -50.degree. C. is carried out and in the course of 30
min. 70.45 ml (112.72 mmol) of butyllithium (1.6M in hexane) is so
added dropwise that the temperature remains between -55.degree. C.
and -45.degree. C. The reaction mixture is then heated in the
course of 15 min. to -5.degree. C. and is maintained at that
temperature for 30 min. It is then cooled to -65.degree. C., 13.09
g (112.72 mmol) of tert-butyl acetate are added dropwise in the
course of 30 min. and stirring is carried out at that temperature
for 40 min. 10.78 g (28.18 mmol) of (E)-5-[3-(4-fluorophenyl)-
-1-isopropyl-1H-indol-2-yl]-3-hydroxypent-4-enoic acid methyl ester
in 50 ml of THF (dried over sodium) are added dropwise in the
course of 30 min. Stirring is then carried out for 1 hour at
-60.degree. C., followed by heating in the course of 45 min. to
-5.degree. C. and leaving at that temperature for 30 min.
Hydrolysis with 65 ml of saturated ammonium chloride solution is
carried out in the course of 3 min. and stirring is carried out for
10 min. The phases are separated and the aqueous phase is extracted
twice with 250 ml of ethyl acetate. The combined organic phases are
washed with 10 ml portions of 1 N HCl until the pH is acidic, and
then with saturated sodium chloride solution until neutral, dried
over magnesium sulfate, filtered and concentrated by evaporation.
An orange product is obtained which, according to NMR, still
contains tert-butyl acetate.
[0108] The enantiomers can be resolved by means of HPLC on a
Chiracel OD column using n-hexane/ethanol=98:2 at a flow rate of 1
ml/min., the retention times being 21.68 and 28.02 min.
EXAMPLE 18
[0109]
Erythro-(+/-)-(E)-7-[3-(4-Fluorophenyl)-1-isopropyl-1H-indol-2-yl]--
3,5-dihydroxyhept-6-enoic acid tert-butyl ester 37
[0110] 100 ml of THF (dried over sodium) are introduced into a
thoroughly heated 500 ml three-necked, round-bottomed flask,
equipped with a magnetic stirrer, thermometer, dropping funnel,
nitrogen delivery line and acetone/dry-ice bath, and cooled under a
nitrogen atmosphere and with stirring to -78.degree. C. 2.05 g
(54.12 mmol) of sodium borohydride are added and stirring is
carried out for 5 min. 40.59 ml (40.59 mmol) of diethyl
methoxyborane (1 M in THF) are added dropwise in the course of 15
min. and stirring is carried out for 15 min. 14.97 g of crude
(E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-5-hydroxy-3-oxohept--
6-enoic acid tert-butyl ester dissolved in 35 ml of THF (dried over
sodium) and 45 ml of methanol (dried over 4 .ANG. molecular sieve)
are then added dropwise in the course of 1 hour so that the
temperature does not exceed -75.degree. C. The reaction mixture is
poured, with stirring, into a mixture of 125 ml of saturated sodium
hydrogen carbonate solution and 125 ml of ethyl acetate. 150 ml of
water are added to the mixture in order to dissolve precipitated
salts, the phases are separated and the aqueous phase is extracted
twice with 250 ml of ethyl acetate. The combined organic phases are
washed four times with 50 ml of saturated sodium chloride solution,
dried over magnesium sulfate, filtered and concentrated by
evaporation. A yellow resin is obtained, which is dissolved in 170
ml of ethyl acetate, and 18.29 g of 30% hydrogen peroxide solution
are added in the course of 20 minutes, the temperature being
maintained at 20.degree. C. by means of a water bath. Stirring is
then carried out for 18 hours at room temperature, 130 ml of
saturated sodium chloride solution are added, the phases are
separated and the organic phase is washed with 130 ml of a 10%
sodium hydrogen sulfite solution so that afterwards a peroxide test
with potassium iodide/starch paper is negative. Washing twice with
50 ml of saturated sodium chloride solution is then carried out,
followed by drying over magnesium sulfate, filtration and
concentration by evaporation. After column chromatography
(hexane/ethyl acetate=3:2), the desired product is obtained, the
syn/anti ratio according to .sup.13C-NMR being>70:1 (see K. M.
Chen, Tetrahedron Letters 28, 155 (1987)).
[0111] The enantiomers can be resolved by means of HPLC on a
Chiracel OD column using n-hexane/ethanol=93:7 at a flow rate of 1
ml/min., the retention times being 6.93 and 8.89 min.
EXAMPLE 19
[0112] Sodium
erythro-(+/-)-(E)-7-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-
-2-yl]-3,5-dihydroxyhept-6-enoate 38
[0113] 0.49 g (1.05 mmol) of
erythro-(+/-)-(E)-7-[3-(4-fluorophenyl)-1-iso-
propyl-1H-indol-2-yl]-3,5-dihydroxyhept-6-enoic acid tert-butyl
ester in 5 ml of ethanol puriss. are introduced into a 10 ml
three-necked, round-bottomed flask, equipped with a magnetic
stirrer, thermometer, septum, injector and nitrogen delivery line,
1.00 ml (1.00 mmol) of 1 N sodium hydroxide solution is added
dropwise and stirring is carried out for 2.5 hours at room
temperature. The clear solution is filtered and diluted with 6 ml
of water and extracted twice with 7 ml of tert-butyl methyl ether.
Approximately 2 ml of water are distilled off and the remaining
solution is lyophilised, yielding a slightly beige powder of which
the NMR corresponds to that of the commercial product.
* * * * *