Process for the preparation of substituted thiazolidinedione

Details Process for the preparation of substituted thiazolidinedione Process for the preparation of substituted thiazolidinedione

2001-11-08

2003-10-14

Solola, T. A. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06632947

ABSTRACT:

This invention relates to a novel process and in particular to a process for preparing certain substituted thiazolidinedione derivatives and to certain intermediates to the substituted thiazolidinedione derivatives
European Patent Application, Publication Number 0306228 discloses certain thiazolidinedione derivatives of formula (A):
or a tautomeric form thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein:
A
a
represents a substituted or unsubstituted aromatic heterocyclyl group;
R
a
represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
R
b
and R
c
each represent hydrogen or R
b
and R
c
together represent a bond;
A
b
represents a benzene ring having in total up to five substituents; and
n′ represents an integer in the range of from 2 to 6.
EP 0306228 also discloses a process for reducing the compounds of formula (A) wherein R
b
and R
c
together represent a bond (the ‘benzylidene thiazolidine-2,4-diones’) to the corresponding compounds of formula (A) wherein R
b
and R
c
each represent hydrogen (the ‘benzylthiazolidine-2,4-diones’). The particular reduction methods disclosed in EP 0306228 are catalytic hydrogenation methods and dissolving metal reduction methods.
Selective reduction of the exocyclic double bond in the benzylidene thiazolidine-2,4-dione moiety by complex hydride reducing agents is not considered to provide the basis for a viable commercial process due to a general expectation that the required selectivity would not be achieved, with particular reference to the aluminium hydrides, and/or that the reaction would give poor yields. We have now surprisingly discovered that a benzylidene thiazolidine-2,4-dione group is selectively reduced to the corresponding benzyl thiazolidine-2,4-dione, by use of a complex hydride reducing agent in a high yielding and commercially viable process.
Accordingly, the present invention provides a process for preparing a compound of formula (I):
or a tautomeric form thereof or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, wherein: J represents O or S; T represents a substituted or unsubstituted aryl group and T
1
is O or S; which process comprises, reducing a compound of formula (II):
or a tautomeric form thereof or a salt thereof or a solvate thereof, wherein T and T
1
are as defined in relation to formula (I), with a complex hydride reducing agent or a source of a complex hydride reducing agent; and thereafter, as required, preparing a pharmaceutically acceptable salt or a pharnaceutically acceptable solvate of the compound of formula (I) or a tautomeric form thereof.
Suitable complex hydride reducing agents include borohydride reducing agents and aluminium hydride reducing agents.
Suitable borohydride reducing agents include diborane and metal borohydrides.
A suitable metal borohydride is an alkali metal borohydride, such as a lithium, sodium or potassium borohydride, especially lithium or potassium.
Borohydrides include unsubstituted and substituted borohydrides.
Suitable substituted borohydrides include borohydrides with up to three substituents on boron selected from such as alkyl and phenyl groups.
Suitable alkyl groups are C
1 6
alkyl groups, such as ethyl and, especially, butyl groups.
Particular butyl groups are sec and tert butyl groups.
Particular borohydride reducing agents are those which comprise the trihydroborane, triethylborane, tributylborane or triphenylborane moiety.
Favoured borohydride reducing agents include lithium tri-sec-butyl borohydride, potassium tri-sec-butyl borohydride/lithium chloride, soditun tri-sec-butyl borohydride, potassium triphenylborohydride, lithium triethylborohydride, lithium borohydride and sodium borohydride.
One preferred borohydride reducing agent is lithium borohydride.
One preferred borohydride reducing agent is lithium tri-sec-butyl borohydride.
When an unsubstituted metal borohydride is used as the reducing agent, it is preferred if the reduction is carried out in the presence of a base such as pyridine a substituted pyridine, quinoline, a substituted quinoline, a secondary or tertiary amine, such as piperidine or triethylamine, or a phosphine such as triphenylphosphine.
Conveniently, the said base is used as a solvent or co-solvent for the reaction.
A preferred base is pyridine.
A suitable aluminium hydride reducing agent is lithium aluminium hydride.
The reaction conditions for the reduction reaction are the appropriate conditions dictated by the nature of the complex hydride reducing agent chosen:
In one aspect, when the reagent is a borohydride reducing reagent suitable solvents include alkanols, such as methanol and ethanol, tetrahydrofuran and pyridine or mixtures thereof.
When the reducing reagent is an alkali metal borohydride a preferred solvent is pyridine/tetrahydrofuran.
When the reducing reagent is an alkali metal trialkyl or triphenyl borohydride, a preferred solvent is tetrahydrofuran.
The borohydride reduction is carried out at a temperature which provides a suitable rate of formation of the required product, usually at ambient or an elevated temperature, suitably at an elevated temperature, preferably above 50° C., for example 65° C. and conveniently at the reflux temperature of the required solvent. Usually the reactants are mixed at ambient temperature and the reaction mixture is heated at the reflux temperature of the solvent.
In a further aspect, when the reagent is an aluminium hydride reducing reagent, suitable solvents include aprotic solvents such as tetrahydrofuran.
The aluminium hydride reduction is carried out at a temperature which provides a suitable rate of formation of the required product, usually at low to ambient temperature, for example a temperature in the range of from −10 to 10° C., suitably in the range of from −5 to 0° C.
It is considered that the reduction of the compounds of formula (II), wherein T
1
is S, especially when the reducing agent is a borohydride reducing agent, proceeds via an intermediate of formula (III):
or a tautomeric form thereof, or salt thereof, or a solvate thereof, wherein J and T are as defined in relation to formula (I).
The intermediate of formula (III) is obtained in better yield when the reduction is carried out at low temperature. Thus, in a further aspect, the present invention provides a process for preparing a compound of the above defined formula (III), which process comprises, reducing a compound of the above defined formula (II) with a metal hydride reducing agent, preferably a borohydride reducing agent, preferably wherein the reaction is carried at low temperature, suitably below ambient temperature, for example between 0° and 5° C.; and thereafter, as required, preparing a salt or a solvate of the compound of formula (III).
A preferred reducing agent for preparing a compound of formula (III) is lithium or potassium tri-sec-butylborohydride (also known as “L-selectride” or “K-selectride”), preferably lithium tri-sec-butylborohydride.
The present invention further provides a compound of the above defined formula (III) or a tautomeric form thereof, or salt thereof, or a solvate thereof, which compound is useful as an intermediate.
The present invention further comprises a process for converting the above defined compound of formula (III) into the above defined compound of formula (I), which process comprises heating the compound of formula (III), suitably in a solvent, and thereafter as required preparing a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate of the compound of formula (I).
Suitable solvents for the said conversion of the compound of formula (III) into compound (I) include those mentioned above for the preparation of the compound of formula (III).
It will be appreciated from the foregoing discussion that the reduction of the compound of formula (II) to provide a compound of formula (I), especially when

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