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:
Aa represents a substituted or unsubstituted aromatic heterocyclyl group;
Ra 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;
Rb and Rc each represent hydrogen or Rb and Rc together represent a bond;
Ab represents a benzene ring having in total up to five substituents; and
nxe2x80x2 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 Rb and Rc together represent a bond (the xe2x80x98benzylidene thiazolidine-2,4-dionesxe2x80x99) to the corresponding compounds of formula (A) wherein Rb and Rc each represent hydrogen (the xe2x80x98benzylthiazolidine-2,4-dionesxe2x80x99). 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 T1 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 T1 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 C1 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 50xc2x0 C., for example 65xc2x0 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 xe2x88x9210 to 10xc2x0 C., suitably in the range of from xe2x88x925 to 0xc2x0 C.
It is considered that the reduction of the compounds of formula (II), wherein T1 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 0xc2x0 and 5xc2x0 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 xe2x80x9cL-selectridexe2x80x9d or xe2x80x9cK-selectridexe2x80x9d), 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 employing borohydride reducing agents, is preferably carried out at a temperature high enough to ensure conversion of the intermediate of formula (III) into the compound of formula (I), suitably the temperature is above 50xc2x0 C., for example 65xc2x0 C. and conveniently the reflux temperature of the reaction solvent.
Suitable general reaction conditions for the borohydride and aluminium hydride reductions are also as described in xe2x80x9cReductions by the Alumino- and Borohydrides in Organic Synthesisxe2x80x9d by J. Seyden-Penne (VCH Publishers, Inc./Lavoisierxe2x80x94Tec and Doc, published 1991) and the references disclosed therein.
The compounds of formula (I) (or (III)) are isolated from the reaction and subsequently purified by use of conventional isolation and purification methods such as chromatography and crystallization/recrystalliazation.
The complex hydride reducing agents of the process are usually commercially available or they can be prepared using conventional procedures, for example the borohydride and aluminium hydride reagents can be prepared using methods such as those described in xe2x80x9cReductions by the Alumino- and Borohydrides in Organic Synthesisxe2x80x9d (ibid) and particularly in the references cited therein.
Certain of the borohydride reducing agents are conveniently prepared in situ. For example, lithium tri-sec-butyl borohydride is conveniently prepared from tri-sec-butyl borane and lithium aluminium hydride.
Also, lithium borohydride is conveniently prepared from sodium borohydride and a lithium salt according to known procedures such as those disclosed in Inorg. Chem. 1981, 20, 4454; J. Am. Chem. Soc. 1953, 75, 209; Nature 1954, 173, 125 and J. Am. Chem. Soc. 1955, 77, 6209.
Suitably T represents a moiety selected from the list consisting of (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip) and (Iq): 
wherein A1, A2, R1 and n are as defined in relation to formula (I) of EP 0306228; 
wherein R2, L1, L2 and L3 are as defined in relation to formula (I) of EP 0008203; 
wherein R1, R2, R3, R4, R5, W and n are as defined in relation to formula (I) of EP(0139421; 
wherein R1, R2 and R3 are as defined in relation to formula (I) of EP 0032128; 
wherein A, R, R1 and X are as defined in relation to formula (I) of EP 0428312; 
when A, B, R and R1 are as defined in relation to formula (II) of EP 0428312; 
wherein R1 is as defined in relation to formula (I) of EP 0489663; 
wherein R1, R2, R3 and n are as defined in relation to formula (I) of EP 0155845; 
when R1 is as defined in relation to formula (I) of EP 0257781; 
wherein Ar, R1, R2, R3, R4, R5, n, U and W are as defined in relation to formula (I) of U.S. Pat. No. 5104888; 
when A, R1, R2 and X are as defined in relation to formula (I) of EP 0208420; 
when R1, R2, X, Z m and n are as defined in relation to formula (I) of EP 0177353; 
according to formula (I) of EP 0319189; 
wherein A, B, X, X1, X2, n and Z are as defined in relation to formula (I) of EP 0332331; 
wherein V, W, X, Y, Z, Z1 and n are as defined in EP 0332332; and 
wherein Q and X are as defined in relation to formula (I) of International Application No. WO 92/18501.
Favourably, T represents a moiety of the above defined formula (Ia), (Ic), (Ie), (If), (Ii), (Ik) or (Io).
In particular T represents a moiety selected from the list consisting of (a), (b), (c), (d), (e), (f), (g), (h) (i) and (j): 
Preferably, T represents a moiety of the above defined formula (Ia).
Preferably, T1 represents S.
Preferably J represents O.
Thus, in a preferred aspect, the invention provides a process for preparing a compound of formula (I) as defined in EP 0306228: Accordingly, the invention provides a process for preparing a compound of formula (IA): 
or a tautomeric form thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein:
A1 represents a substituted or unsubstituted aromatic heterocyclyl group;
R1 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;
A2 represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6; which process comprises, treating a compound of formula (IIB): 
or a tautomeric form thereof or a salt thereof, or a solvate thereof, wherein A1, A2, R1 and n are as defined in relation to formula (IA) with a complex hydride reducing agent or a source of a complex hydride reducing agent, such as a borohydride reducing agent or a source of a borohydride reducing agent; and thereafter, as required, preparing a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate of the compound of formula (IA) or a tautomeric form thereof.
In a preferred aspect, the compound of formula (HII) is a compound of formula (IIIA): 
wherein A1, A2, R1 and n are as defined in relation to formula (IA) herein.
Unless mentioned to the contrary herein, the suitable, apt, favoured and preferred values for each variable in the above mentioned moieties of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io) or (Ip) are as defined in the European and International patent applications or United States patents mentioned above in respect of each of the said formulae.
In particular, the suitable, apt, favoured and preferred values of the variables A1, A2, R1 and n in formulae (IA), (IIB) and (IIIA) are as defined in relation to formula (I) of EP 0306228.
A most preferred value of A1 in formulae (IA), (IIB) and (IIIA) is a 2-pyridyl group.
A most preferred value of A2 in formulae (IA), (IIB) and (IIIA) is a moiety of formula: 
A most preferred value of R1 in formulae (IA), (IIB) and (IIIA) is a methyl group.
A most preferred value of n in formulae (IA), (IIB) and (IIIA) is 2.
Most favourably, T represents a moiety of the above defined formula (a), (c) or (d).
A preferred value of T is a moiety of the above defined formula (a).
A most preferred value of formula (IA) is 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione, or a tautomeric form thereof or a salt thereof, or a solvate thereof.
A most preferred value of formula (IIB) is 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedione or a tautomeric form thereof or a salt thereof, or a solvate thereof.
When the reaction comprises a compound of formula (IIB) as substrate it is preferred if the reaction is carried out at an elevated temperature, preferably above 50xc2x0 C., for example at 65xc2x0 C.
A preferred example of a compound of formula (IIIB) is 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-5-{1-[2,4-dioxothiazolidin-5-yl]-1-[4-(2-(N-methyl-N-(2-pyridyl)amino)ethoxy)phenyl]methyl}-2,4 thiazolidinedione.
Suitable salts are pharmaceutically acceptable salts.
Suitable solvates are pharmaceutically acceptable solvates.
Unless mentioned to the contrary herein, the suitable, apt, favoured and preferred pharmaceutically acceptable salts, pharmaceutically acceptable solvates and tautomeric forms of each of the compounds in the above mentioned moieties of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io) or (Ip) are as defined in the European or International patent applications or United States patents mentioned above in respect of each of the said formulae.
In particular it should be mentioned that suitable pharmaceutically acceptable salts include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-b-phenethylamine, dehydroabietylamine, N,Nxe2x80x2-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline.
In addition should be mentioned those pharmaceutically acceptable salts provided by pharmaceutically acceptable acids including mineral acids, for example for compounds of formula (I) wherein T represents a moiety of formula (Ia) suitable salts are those disclosed in WO 94/05659 including salts provided by mineral acids, such as hydrobromic, hydrochloric and sulphuric acids, and organic acids, such as methanesulphonic, tartaric and maleic acids, especially tartaric and maleic acid.
The compounds of formula (II) may be prepared according to known methods, for example by use of the appropriate method disclosed in the abovementioned European and International patent applications or United States patents. The contents of the abovementioned European and International patent applications and United States patents are incorporated herein by reference.
In particular compounds of formula (IIB) may be prepared according to the methods disclosed in EP 0306228.
The following examples illustrate the invention but do not limit it in any way.
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