Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-22
2004-06-01
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06743926
ABSTRACT:
The present invention relates to a process for the preparation of indole derivatives and to novel intermediates.
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.
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.
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.
The present invention thus relates to a process for the preparation of compounds of formula
wherein R
1
is C
1
-C
6
alkyl and
X is hydrogen, a hydrocarbon radical or a cation,
in which process a compound of formula
wherein R
1
is as defined above and R
2
is hydrogen or a hydrocarbon radical, is reduced, the resulting compound of formula
wherein R
1
and R
2
are as defined above, is reacted with a compound that introduces the radical of formula —CH
2
—COOR
3
wherein R
3
has the meanings given above for R
2
, and the resulting compound of formula
is reduced and optionally hydrolysed.
There come into consideration as C
1
-C
6
alkyl radicals for R
1
, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, and straight-chain or branched pentyl or hexyl. C
1
-C
4
Alkyl radicals are preferred. R
1
is preferably propyl, especially isopropyl.
There come into consideration as hydrocarbon radicals for R
2
, R
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
1
-C
12
alkyl, C
3
-C
12
-alkenyl, C
3
-C
12
alkynyl and phenyl radicals. Preferably, R
2
, R
3
and X are each independently of the others unsubstituted or substituted alkyl radicals, especially C
1
-C
12
alkyl radicals and preferably C
1
-C
6
alkyl 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
2
, R
3
and X methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, allyl, benzyl, nitrobenzyl and also hydroxybenzyl. R
2
, R
3
and X are especially preferably C
1
-C
4
alkyl. R
2
is more especially preferably methyl or ethyl, especially methyl. R
3
and X are more especially preferably butyl, especially tert-butyl.
When the radical X is a cation, it may be, for example, sodium or potassium, especially sodium.
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° C. Preferably, the reaction is carried out in an inert gas atmosphere.
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
3
—COOR
3
, such as tert-butyl acetate, may be used as the compound that introduces the radical of formula —CH
2
—COOR
3
, R
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
3
—COOR
3
is formed. The reaction is usually performed in an anhydrous, inert organic solvent, for example an ether, such as diethyl ether, 1,2-dimethoxyethane, 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° 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° C.
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° 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
4
in the presence of triethylboranes as complexing agents, as described in U.S. Pat. No. 4,739,073.
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° 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.
The compounds of formula (2) are novel and can be obtained, for example, according to the following processes:
According to a process variant a) for the preparation of compounds of formula (2), a compound of formula
wherein R
1
has the meanings and preferred meanings given hereinbefore and Y is bromine, chlorine, iodine, —OSO
2
CF
3
or —COCl, especially bromine,
is reacted with a compound that introduces the radical of formula —CH═CH—Z, wherein
Z is the radical —COOR
4
, —COR
5
or —CN, R
4
is hydrogen or a hydrocarbon radical and R
5
is a hydrocarbon radical or unsubstituted or substituted amino,
and the resulting compound of formula
optionally after conversion of the compound of formula (6) wherein Z is the radical —COOR
4
into the corresponding acid chloride or into the free acid,
is reacted with a compound that introduces the radical of formula —CH
2
—COOR
2
.
When R
4
and R
5
are hydrocarbon radicals, the meanings and preferred meanings for hydrocarbon radicals given hereinbefore for R
2
apply. For R
5
as unsubstituted or substituted amino there comes into consideration, for example, amin
Wolleb Annemarie
Wolleb Heinz
Ciba Specialty Chemicals Corporation
Mansfield Kevin T.
McKane Joseph K.
Wright Sonya
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