U.S. patent application number 11/326003 was filed with the patent office on 2006-05-18 for process for the preparation of thiazolidinedione derivatives.
This patent application is currently assigned to SmithKline Beecham plc. Invention is credited to Robert Gordon Giles, Norman John Lewis, John Kirby Quick.
Application Number | 20060106221 11/326003 |
Document ID | / |
Family ID | 10821570 |
Filed Date | 2006-05-18 |
United States Patent
Application |
20060106221 |
Kind Code |
A1 |
Giles; Robert Gordon ; et
al. |
May 18, 2006 |
Process for the preparation of thiazolidinedione derivatives
Abstract
A process for preparing a compound of formula (I): ##STR1## or a
tautomeric form thereof or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate thereof, wherein:
A.sup.1 represents a substituted or unsubstituted aromatic
heterocyclyl group; R.sup.1 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; A.sup.2 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 catalytically reducing a compound
of formula (II): ##STR2## wherein A.sup.1, R.sup.1, A.sup.2 and n
are as defined in relation to formula (I), characterised in that
the reduction reaction is carried out using a hydrogen pressure
above 20 psi; and thereafter if required forming a pharmaceutically
acceptable salt and/or a pharmaceutically acceptable solvate of the
compound of formula (I).
Inventors: |
Giles; Robert Gordon;
(Tonbridge, GB) ; Lewis; Norman John; (Tunbridge
Wells, GB) ; Quick; John Kirby; (Crowborough,
GB) |
Correspondence
Address: |
GLAXOSMITHKLINE;Corporate Intellectual Property - UW 2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham plc
|
Family ID: |
10821570 |
Appl. No.: |
11/326003 |
Filed: |
January 5, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10288072 |
Nov 4, 2002 |
|
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|
11326003 |
Jan 5, 2006 |
|
|
|
10082995 |
Feb 26, 2002 |
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10288072 |
Nov 4, 2002 |
|
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09530888 |
Jul 10, 2000 |
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PCT/EP98/06997 |
Oct 27, 1998 |
|
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|
10082995 |
Feb 26, 2002 |
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Current U.S.
Class: |
546/269.7 |
Current CPC
Class: |
C07D 417/12
20130101 |
Class at
Publication: |
546/269.7 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 417/02 20060101 C07D417/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 4, 1997 |
GB |
9723295.3 |
Claims
1-10. (canceled)
11. A process for preparing a compound selected from
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione-
, or a tautomeric form thereof, or a pharmaceutical acceptable salt
thereof or a pharmaceutically acceptable solvate thereof,
comprising catalytically reducing
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione, or a tautomeric form thereof, or a salt thereof, or a
solvate thereof, at a temperature above 70.degree. C. using a
hydrogen pressure above 20 psi, and thereafter optionally forming a
pharmaceutically acceptable salt or a pharmaceutically acceptable
solvate of
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione-
, or a tautomeric form thereof.
12. The process according to claim 11, wherein the hydrogen
pressure is in the range of from 50 to 1500 psi.
13. The process according to claim 11, wherein the hydrogen
pressure is in the range of from 70 to 1000 psi.
14. The process according to claim 11, wherein the hydrogen
pressure is in the range of from 70 to 80 psi.
15. The process according to claim 11, wherein the catalyst is a
palladium catalyst.
16. The process according to claim 15, wherein the catalyst
comprises a palladium-on-carbon catalyst.
17. The process according to claim 15, wherein the catalyst
comprises a 5-10% palladium-on-carbon catalyst.
18. The process according to claim 15, wherein the catalyst loading
is 10 to 50 wt/wt %.
19. The process according to claim 15, wherein the catalyst loading
is 25 to 50 wt/wt %.
20. The process according to claim 11, wherein the reduction is
conducted at a temperature in the range of from 80.degree. to
115.degree. C.
21. The process according to claim 11, wherein
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione, or a tautomeric form thereof is catalytically reduced.
22. The process according to claim 11, wherein a salt of
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione, or a tautomeric form thereof is catalytically reduced.
23. The process according to claim 22, wherein a mineral acid salt
of
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione, or a tautomeric form thereof is catalytically reduced.
24. The process according to claim 23, wherein the mineral acid is
hydrobromic acid, hydrochloric acid, or sulphuric acid.
25. The process according to claim 22, wherein an organic acid salt
of
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione, or a tautomeric form thereof is catalytically reduced.
26. The process according to claim 25, wherein the organic acid is
methanesulphonic acid or tartaric acid.
Description
[0001] This application is a divisional of U.S. application Ser.
No. 10/288,072, filed Nov. 4, 2002, which is a continuation of U.S.
application Ser. No. 10/082,995, filed Feb. 26, 2002, which is a
continuation of U.S. application Ser. No. 09/530,888, filed Jul.
10, 2000, which is a 371 of International Application No.
PCT/EP98/06997, filed Oct. 27, 1998.
[0002] This invention relates to a novel process and in particular
to a process for preparing certain substituted thiazolidinedione
derivatives.
[0003] European Patent Application, Publication Number 0306228
discloses certain thiazolidinedione derivatives of formula (A):
##STR3## or a tautomeric form thereof or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate
thereof, wherein: A.sup.a represents a substituted or unsubstituted
aromatic heterocyclyl group; R.sup.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.sup.b and R.sup.c each represent
hydrogen or R.sup.b and R.sup.c together represent a bond; A.sup.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.
[0004] EP 0306228 also discloses a process for reducing the
compounds of formula (A) wherein R.sup.b and R.sup.c together
represent a bond (the `benzylidene thiazolidine-2,4-diones`) to the
corresponding compounds of formula (A) wherein R.sup.b and R.sup.c
each represent hydrogen (the `benzylthiazolidine-2,4-diones`). The
particular reduction methods disclosed in EP 0306228 are dissolving
metal methods and catalytic hydrogenation methods.
[0005] It has now been discovered that when the catalytic
hydrogenation of the benzylidene thiazolidine-2,4-diones is carried
out using an elevated pressure of hydrogen that the reaction can be
effected with a surprising reduction in the catalytic loading and
reaction time and, most surprisingly, produces a significant
reduction in by-product formation.
[0006] Accordingly, the present invention provides a process for
preparing a compound of formula (I): ##STR4## or a tautomeric form
thereof or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, wherein: A.sup.1
represents a substituted or unsubstituted aromatic heterocyclyl
group; R.sup.1 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;
A.sup.2 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 catalytically reducing a compound of
formula (II): ##STR5## wherein A.sup.1, R.sup.1, A.sup.2 and n are
as defined in relation to formula (I), characterised in that the
reduction reaction is carried out using a hydrogen pressure above
20 psi, and thereafter, if required, forming a pharmaceutically
acceptable salt and/or a pharmaceutically acceptable solvate of the
compound of formula (I).
[0007] Suitably the reaction is carried out at a pressure in the
range of from 50 to 1500 psi, such as 60 to 1500 psi, 75 to 1500
psi, 200 to 1500 psi, 70 to 1000 psi or 200 to 1000 psi, suitably
70 to 1000 psi.
[0008] Examples of reaction pressures include 70, 75, 80, 500 and
1000 psi.
[0009] A suitable hydrogenation catalyst is a noble metal catalyst,
suitably a palladium catalyst.
[0010] Favoured catalysts are supported noble metal catalysts, such
as a palladium-on-carbon catalyst, typically comprising 5% to 10%
of palladium.
[0011] A preferred catalyst is a 10% palladium-on-carbon
catalyst.
[0012] Catalyst loadings (expressed as w/w % of catalyst to
substrate) in the reaction are typically in the range of from 5 to
100%, usually 10 to 50% and preferably 25 to 50%.
[0013] The reaction may be carried out using any suitable solvent
such as acetic acid, or an alkanol, such as methanol or ethanol,
preferably admixed with an aqueous mineral acid such as
hydrochloric acid; or tetrahydrofuran, preferably admixed with an
aqueous mineral acid such as hydrochloric acid. Preferably the
solvent is acetic acid or aqueous acetic acid, for example a 1:2
acetic acid:water mixture.
[0014] The reaction is carried out at a temperature which provides
a suitable rate of formation of the required product, suitably at
an elevated temperature, preferably above 70.degree. C., for
example in the range of from 80.degree. C. to 115.degree. C.
[0015] The compounds of formula (I) are isolated from the reaction
and subsequently purified by use of conventional isolation and
purification methods such as chromatography and
crystallization/recrystalliazation.
[0016] The suitable, apt, favoured and preferred values of the
variables A.sup.1, A.sup.2, R.sup.1 and n in formulae (I) and (II)
are as defined in relation to formula (I) of EP 0306228.
[0017] A most preferred value of A.sup.1 is a 2-pyridyl group.
[0018] A most preferred value of A.sup.2 is a moiety of formula:
##STR6##
[0019] A most preferred value of R.sup.1 is a methyl group.
[0020] A most preferred value of n is 2.
[0021] A most preferred value of formula (I) 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.
[0022] Crystalline
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione is isolated from the present reaction and as such forms a
further aspect of the present invention. A suitable
crystallization/recrystallization solvent is denatured ethanol, the
crystallization is favourably effected from refluxing solvent which
is allowed to cool to provide the required compound.
[0023] A most preferred value of formula (II) is
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidine-
dione or a tautomeric form thereof or a salt thereof, or a solvate
thereof.
[0024] Suitable salts are pharmaceutically acceptable salts.
[0025] 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)-anine, cycloalkylamines such as
bicyclohexylamine, or with procaine, dibenzylpiperidine,
N-benzyl-b-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases
of the pyridine type such as pyridine, collidine or quinoline.
[0026] In addition should be mentioned those pharmaceutically
acceptable salts provided by pharmaceutically acceptable acids
including mineral acids, 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. A preferred salt is a maleate
salt.
[0027] Suitable solvates are pharmaceutically acceptable solvates,
such as hydrates.
[0028] The compounds of formula (II) are prepared according to
known methods, for example by use of the appropriate method
disclosed in EP 0306228. The contents of EP 0306228 are
incorporated herein by reference.
[0029] The following example illustrates the invention but does not
limit it in any way.
EXAMPLE
Reduction of
(Z)-5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazoli-
dinedione to
5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione
[0030] To a solution of
(Z)-5-{[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazol-
idinedione (123 kg) in glacial acetic acid (1232 L) is added 10%
palladium on charcoal (Johnson-Matthey type 87L, 123 kg, catalyst
contains .about.50% w/w water and hence the catalyst loading was
50% w/w). The resulting mixture is hydrogenated at 70-80 p.s.i.
hydrogen pressure at about 95.degree. C. After the starting
material is consumed (15-20 hours), the reaction mixture is cooled
to about 65.degree. C. and the catalyst is removed by filtration.
The resulting solution is concentrated under reduced pressure to
low volume and the residue is dissolved in denatured ethanol (500
L) at 60.degree. C. The solution is heated to reflux and then
cooled to ambient temperature to effect crystallisation. The
product,
5-{[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedion-
e, is isolated by filtration, and dried in vacuo at 45.degree. C.
Typical yields are 70-80%.
Effect of Change of Reaction Pressure
[0031] The above reaction can be performed over a range of
pressures resulting in a significant reduction in reaction time and
catalyst loading, as shown below. TABLE-US-00001 Reaction number
Conditions Reaction Time (hours.) 1 (75 psi, 100% catalyst) 15-20 2
1000 psi, 100% catalyst <2 3 1000 psi, 50% catalyst 7 4 500 psi,
100% catalyst 4 5 500 psi, 50% catalyst ca. 12
* * * * *