Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
1999-05-10
2004-08-10
Qazi, Sabiha (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C560S008000, C544S248000, C544S252000, C054S084000, C054S085000, C054S085000, C054S087000, C548S427000
Reexamination Certificate
active
06774236
ABSTRACT:
The invention relates to a process for the preparation of enantiomerically pure cycloalkano-indolecarboxylic acids and azaindolecarboxylic acids and pyrimido[1,2a]indolecarboxylic acids and their activated derivatives, which represent important intermediates for the synthesis of antiatherosclerotically active cycloalkanoindole derivatives and azaindole derivatives and pyrimido[1,2a]indole derivatives.
It is known that enantiomerically pure cycloalkano-indolecarboxylic acids and azaindole-carboxylic acids and their activated derivatives can be separated into the corresponding enantiomers by diastereomeric separation by conventional methods, for example by chromatography or fractional crystallization.
This process has a number of disadvantages: both the chromatographic diastereomeric separation and the fractional crystallization of the diastereomers are associated with high equipment requirements. In addition, in this case, generally 50% of the “wrong” diastereomer arises, which can no longer be recycled to the original preparation process.
This 50% loss of yield considerably impairs the economic efficiency of a (large) industrial-scale process, quite apart from the fact that 50% of “by-product” must be disposed of. Furthermore, the customary chiral auxiliary reagents are generally very expensive even in small amounts and can then usually only be prepared via a complex synthetic pathway.
It has now been found that enantiomerically pure cycloalkano-indolecarboxylic acids and azaindolecarboxylic acids and pyrimido[1,2a]indole-carboxylic acids and their activated derivates of the general formula (I)
in which
A represents a radical of the formula
or
J, D, E, G, L and M are identical or different and denote hydrogen, halogen, trifluoromethyl, carboxyl, hydroxyl, linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or linear or branched alkyl having up to 6 carbon atoms, which itself can be substituted by hydroxyl or by linear or branched alkoxy having up to 4 carbon atoms,
in which
R
1
and R
2
, including the double bond linking them, together form a phenyl ring or pyridyl ring or a ring of the formula
where
R
5
denotes hydrogen or linear or branched alkyl having up to 4 carbon atoms,
R
3
and R
4
, including the double bond linking them, together form a phenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical, where all the ring systems listed under R
1
/R
2
and R
3
/R
4
are optionally up to trisubstituted identically or differently by halogen, trifluoromethyl, carboxyl, hydroxyl, by linear or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or by linear or branched alkyl having up to 6 carbon atoms, which itself can be substituted by hydroxyl or by linear or branched alkoxy having up to 4 carbon atoms,
T represents cycloalkyl having 4 to 12 carbon atoms, or represents linear or branched alkyl having up to 12 carbon atoms,
Q represents hydroxyl or an activating radical,
and their salts are obtained
by firstly converting compounds of the general formula (II),
in which
R
6
together with the oxygen atom represents a chiral alcohol radical, by means of compounds of the general formula (III)
T—Z (III)
in which
T has the meaning specified and
Z represents a typical leaving group, such as bromine, chlorine, iodine, mesyl, tosyl, or trifluoromethylsulphonyl, preferably iodine or bromine,
n inert solvents in the presence of a base by diastereoselective alkylation into the enantiomerically pure compounds of the general formula (IV)
in which
T and R
6
have the meaning specified,
then converting these, by halogenation, into the enantiomerically pure compounds of the general formula (V)
in which
T and R
6
have the meaning specified
and
R
7
represents halogen, such as chlorine, bromine, iodine, preferably bromine, reacting these in a further step with compounds of the general formula (VI)
A—H (VI)
in which
R
1
, R
2
, R
3
and R
4
have the meaning specified,
to give the enantiomerically pure compounds of the general formula (VII)
in which
A, T and R
6
have the meaning specified,
and, in the case of compounds of the general formula (I) where Q═OH, carrying out a hydrolysis, and in the case where Q=activating radical, starting from the enantiomerically pure acids reacting with activating reagents.
These can be reacted in a further step with D- or L-phenylglycinol to give compounds of the general formula (VIII)
where these are in this case active compounds for medicaments.
The process according to the invention can be described by way of example by the following formula diagram:
Surprisingly, the process according to the invention gives the wanted enantiomerically pure cycloalkano-indolecarboxylic acids and azaindole-carboxylic acids and pyrimido-indolecarboxylic acids and their activated derivatives without great equipment requirements in very good yields and high purity.
Depending on the configuration of the radical R
6
and stearic effects of the alkyl halide (II) used, the alkylation of the compound (II) proceeds in high yields and in a simple manner diastereoselectively for the first time. The compounds (IV) arise with high diastereomeric excess and crystallize out of the reaction mixture directly, as a result of which even the simple crystallization of crude products gives the compounds of the formula (IV) in diastereomerically pure form.
A further advantage of the process according to the invention is that, by suitable choice of the solvent and a base, the unwanted diastereomer can be epimerized to the desired diastereomer, which in turn crystallizes out directly. Thus, further (wanted) diastereomerically pure product can be produced from the mother liquors by repeated epimerization and crystallization. Direct addition of the mother liquors to the alkylation step can optimize the entire process in the form of a cyclic process.
A further advantage of the process according to the invention is that the halogenated compounds of the general formula (V) surprisingly react with the compounds of the general formula (VI) without racemization at the carbon atom in the 2 position to the carboxylic acid function, to give the compounds of the general formula (VII).
A further advantage of the process according to the invention is the racemization-free reaction at the carbon atom at the 2 position to the carboxylic acid function of the compounds of the general formula (I) where Q=activated radical, preferably chlorine, to give the compounds of the general formula (VIII).
Furthermore, it is a great advantage of the process according to the invention that the starting compounds are very readily accessible. They may be prepared in good yields from relatively simple building blocks with low equipment requirements. Furthermore, the process according to the invention enables amounts of known racemates of the compounds of the general formula (I) present to be converted into the corresponding enantiomers. The process according to the invention enables the preparation of the compounds according to the invention of the general formula (I) using few synthetic stages and in a considerably higher overall yield than by processes known from the prior art.
R
6
, in the context of the above specified definition, represents a chiral alcohol radical, such as (+)- or (−)-menthyl, (+)- or (−)-bornyl, (+)- or (−)-isobornyl or (−)-8-phenylmenthyl. Preferably, R
9
represents (+)- or (−)-menthyl.
Activating radicals (Q), in the context of the invention, generally represent chloride, bromide, mesylate, tosylate or trifluoride. Preference is given to chloride. Preferably, by the process according to the invention, compounds of the general formula (I) are prepared, in which
A represents a radical of the formula
in which
J, D, E, G, L and M are identical or different and denote hydrogen, fluorine, chlorine, bromine trifluoromethyl, carboxyl, hydroxyl, linear or branched alkoxy or alkoxycarbonyl each having up to 4 carb
Fey Peter
Laak Kai Van
Lenfers Jan-Bernd
Naab Paul
Bayer Aktiengesellschaft
Norris McLaughlin & Marcus PA
Qazi Sabiha
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