Reduction method for substituted 5-methylene-thiazolidinediones

The present invention provides a method for making known pharmaceutical compounds. More particularly the present invention provides a new reduction method for making thiazolidinedione derivatives, particularly ciglitazone, pioglitazone, and englitazone. This reduction method comprises reacting a compound of the formula II with a cobalt ion, a ligand and a reducing agent to achieve a compound of the formula I. ##STR1##

The present invention provides a new method of making organic compounds. In 
particular, the present invention provides a new reduction method for 
making certain pharmaceutically active compounds, such as 
thiazolidinedione derivatives, including pioglitazone, ciglitazone, 
englitazone and CS-045. These compounds are known for the treatment of 
diabetes and as insulin sensitizing agents. 
BACKGROUND 
Pioglitazone hydrochloride 
((.+-.)-5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione 
monohydrochloride), a thiazolidinedione derivative, is currently under 
clinical evaluation and is expected to effectively ameliorate the abnormal 
glucose and lipid metabolism associated with NIDDM or obesity (cf. Y. 
Momose et al., Chem. Pharm. Bull., 39:1440 (1991)). 
T. Sohda, et al., J. Med. Chem. 35:2617-2626 (1992), discloses additional 
thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic 
agents. including 
5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione 
, which had the most potent activity, more than 100 times that of 
pioglitazone. 
Another thiazolidine derivative under-going clinical studies as a 
hypoglycemic agent is englitazone sodium, 
5-([3,4-dihydro-2-(phenylmethyl)-2H- 
1-benzopyran-6-yl[methyl]-2,4-thiazolidinedione sodium salt) (cf. D. A. 
Clark et al., J. Med. Chem., 34:319-325 (1991)). 
Ciglitazone ((.+-.)-5- [4- 
[(1-methylcyclohexyl)methoxy]benzyl]-2,4-thiazolidinedione) is 
characteristic of a new class of thiazolidine antidiabetic agents which 
lower blood glucose in animal models of noninsulin diabetes mellitus 
(NIDDM), while actually reducing circulating concentrations of insulin. 
This is believed to be accomplished by improving the responsiveness of the 
peripheral tissues to insulin. See, e.g., Chang, et al, Diabetes 
32:830-838 (September 1983). 
CS-045 is an antidiabetic, thiazolidinedione derivative. Its activity and 
preparation are described in Drugs Fut. 1991, 16(9). 
Also, thiazolidine derivatives useful for the treatment of diabetes are 
described in U.S. Pat. Nos. 4,287,200; 4,687,777; and 4,572,9 12. Their 
effect on insulin resistance are described, e.g. in, Chang, et al, 
Diabetes 32:839-845 (1983) and Chang, et al. Diabetes 32:830-838 (1983). 
The preparation of these thiazolidinedione derivatives, especially 
pioglitazone hydrochloride, includes the reduction of an intermediate 
previously performed by a troublesome high pressure hydrogenation on a 
palladium on carbon catalyst. What is needed in the art is an easier, more 
efficient method for perfoming this reduction. 
INFORMATION DISCLOSURE 
Y. Momose et at., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., 
Japan. Patent 139182 (1988); Chem. Abstr., 109:6504h (1988); disclose the 
process for making thiazolidinedione-derivatives, including pioglitazone, 
using hydrogen on a palladium on carbon catalyst. 
D. A. Clark et at., J. Med. Chem., 34:319-325 (1991) discloses the process 
for making substituted dihydrobenzopyran and dihydrobenzofuran 
thiazolidine-2,4-diones, including englitazone, using hydrogen on a 
palladium on carbon catalyst. 
Drugs Fut. 1991, 16(9) discloses the multistep process, via carbon 
alkylation, for the preparation of the thiazolidinedione CS-045. 
The following references disclose cobalt catalyzed reductions: U. 
Leutenegger et al., Angew. Chem. Int. Ed., 28:60 (1989) discloses the 
enantioselective reduction of .alpha.,.beta.-unsaturated carboxylates with 
sodium borohydride and catalytic amounts of chiral cobalt semicorrin 
complexes; and M. N. Ricroch and A. Gaudemer, J. Organometal. Chem., 
67:119 (1974) discloses (pyridinato) cobaloxime, chloro (pyridinato) 
cobaloxime and vitamin B .sub.12 catalyzing the hydrogenation of 
.alpha.,.beta.-unsaturated esters by hydrogen or sodium borohydride. 
J. O. Oshy, et al., J.A.C.S. 108:67-72 (1986), discloses cobalt 
(II)-mediated sodium borohydride and lithium aluminum hydride reductions, 
which do not involve the use of ligands. 
SUMMARY OF THE INVENTION 
The present invention particularly provides: 
A process for preparing a compound of the formula I (refer to Formula Chart 
below) 
wherein X.sub.1 is an organic residue; which comprises: 
(a) reacting a compound of the formula II with a cobalt ion, a ligand and a 
reducing agent; 
This process wherein the temperature is -20.degree. to 45.degree. C. and 
wherein a suitable solvent is used; 
This process wherein X.sub.1 is the residue of an antidiabetic compound; 
This process wherein X.sub.1 is 
(a) aryl, or 
(b) Het; 
wherein aryl is phenyl or naphthyl substituted by zero to three of the 
following: 
(a) C.sub.1 -C.sub.3 alkyl, 
(b) hydroxy, 
(c) C.sub.1 -C.sub.3 alkoxy, 
(d) halo, 
(e) amino, 
(f) mono- or di-C.sub.1 -C.sub.3 alkylamino, 
(g) nitro, 
(h) mercapto, 
(i) C.sub.1 -C.sub.3 alkylthio, 
(j) C.sub.1 -C.sub.3 alkylsulfinyl, 
(k) C.sub.1 -C.sub.3 alkylsulfonyl, 
(l) --NH--C.sub.1 -C.sub.3 alkylsulfonyl, 
(m) --NC.sub.1 -C.sub.3 alkyl-C.sub.1 -C.sub.3 alkylsulfonyl, 
(n) SO.sub.3 H, 
(o) SO.sub.2 NH.sub.2, 
(p) --CH.sub.2 NH.sub.2, 
(q) --A.sub.1 --(CH.sub.2).sub.n -Het, 
(r) --A.sub.1 --(CH.sub.2).sub.n -(C.sub.1 -C.sub.6 alkyl substituted 
cyclohexyl), or 
(s) --A.sub.1 --(CH.sub.2).sub.n - cyclohexyl; 
wherein A.sub.1 is 
(a) O, or 
(b) S; 
wherein Het is a 5- or 6-membered saturated or unsaturated ring containing 
from one to three heteroatoms selected from the group consisting of 
nitrogen, oxygen, and sulfur; and including any bicyclic group in which 
any of the above heterocyclic rings is fused to a phenyl ring; which 
heterocycle ring is substituted by zero to three of the following: 
(a) C.sub.1 -C.sub.6 alkyl, 
(b) hydroxy, 
(c) hydroxy (C.sub.1 -C.sub.5 alkyl), 
(d) halogen, 
(e) amino, 
(f) amino (C.sub.1 -C.sub.5 alkyl), 
(g) nitro, 
(h) mercapto, 
(i) mercapto (C.sub.1 -C.sub.5 alkyl), 
(j) --SO.sub.3 H, 
(k) --SO.sub.2 NH.sub.2, 
(l) --O--C.sub.1 -C.sub.5 alkyl, 
(m) --(CH.sub.2).sub.n - aryl, or 
(n) --(CH.sub.2).sub.n - cyclohexyl; 
wherein n is zero to five, inclusive; 
This process wherein X.sub.l is the moiety of formula III (refer to Formula 
Chart below) wherein 
R.sub.1 is hydrogen; 
wherein 
R.sub.2 is 
(a) --O--(CH.sub.2)-(5-ethyl-2-pyridyl), 
(b) --O--CH.sub.2 -(1-methylcyclohexyl), 
(c) the moiety of formula IV (refer to Formula Chart below); or 
wherein R.sub.1 and R.sub.2 taken together are the moiety of formula V 
(refer to Formula Chart below); 
This process wherein X.sub.l is the moiety of formula VI (refer to Formula 
Chart below); 
This process wherein the cobalt ion is in the form of 
(a) cobaltous chloride, 
(b) cobaltous diacetate, or 
(c) cobaltic chloride; 
wherein the ligand is 
(a) dimethylglyoxime, 
(b) 2,2'-bipyridyl, or 
(c) 1,10-phenanthroline; 
wherein the reducing agent is 
(a) sodium borohydride, 
(b) lithium borohydride, 
(c) potassium borohydride, 
(d) tetraalkylammonium borohydride, or 
(e) zinc borohydride; 
This process wherein the cobalt ion is in the form of cobaltous chloride, 
the ligand is dimethylglyoxime and the reducing agent is sodium 
borohydride; 
This process wherein the solvent is 
(a) methanol, 
(b) ethanol, 
(c) i-propanol, 
(d) acetone, 
(e) dimethylformamide, or 
(f) tetrahydrofuran; 
provided, however, that if (d), (e) or (f) is the solvent, (a), (b), (c) or 
water must also be present; 
This process wherein the temperature is 5.degree. to 20.degree. C. and the 
solvent is water and tetrahydrofuran; 
This process wherein X.sub.1 is the moiety of formula VI (refer to Formula 
Chart below); 
This process which further comprises: 
(b) reacting the compound of the formula I (refer to Formula Chart below) 
with hydrochloric acid to obtain a compound of the formula VII (refer to 
Formula Chart below. 
Previously, the preparation of thiazolidinedione derivatives included the 
reduction of an intermediate done as a troublesome high pressure 
hydrogenation on a palladium on carbon catalyst. Surprisingly and 
unexpectedly, the present invention provides a new, more efficient method 
for performing this reduction which uses a cobaltous chloride/bidentate 
ligand/sodium borohydride catalyst system and the variations thereof as 
described below. This new reduction method is faster and easier and 
results in improved yield of the desired product. It is also more 
convenient to scale into production equipment since no high pressure 
apparatus is required. 
By "organic residue" is meant the residue of an organic compound that would 
be compatible with the reaction conditions of the process of the present 
invention. Preferably, such a residue will be one that does not react with 
the reactants of the process of the present invention so that only the 
double bond at the 5-position of the thiazolidinedione ring will be 
reduced. The reactants of the present invention include a cobalt ion, a 
ligand and a reducing agent. Such an organic residue would be readily 
determined by one of ordinary skill in the chemical arts. 
By "residue of an antidiabetic compound" is meant the organic moiety that 
is attached to the 5-position of a thiazolidinedione derivative, which 
derivative has antidiabetic activity, such as those described in Y. Momose 
et al., Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. 
Patent 139182 (1988); Chem. Abstr., 109:6504h (1988); D. A. Clark et al., 
J. Med. Chem., 34:319-325 (1991); U.S. Pat. Nos. 4,287,200; 4,687,777; and 
4,572,912; Drugs Fut 1991, 16(9); and J. Med. Chem. 35:2617-2626 (1992). 
The description of the preparation of the intermediates of these compounds 
of formula II is expressly incorporated by reference herein. The process 
of the present invention is preferably applicable to the commercially 
important thiazolidinediones, pioglitazone hydrochloride (the compound of 
formula VII in the Formula Chart,) ciglitazone (the compound of formula X 
in the Formula Chart), englitazone (the compound of formula XX in the 
Formula Chart), CS-045 (the compound of formula XXX in the Formula Chart) 
and the recently disclosed thiazolidinedione of formula XL. All of the 
intermediates of formula II may readily be prepared by procedures 
analogous to those described above by one of ordinary skill in the art. 
By "aryl" is meant phenyl or naphthyl substituted by zero to three of the 
following: C.sub.1 -C.sub.3 alkyl, hydroxy, C.sub.1 -C.sub.3 alkoxy, halo, 
amino, mono- or di-C.sub.1 -C.sub.3 alkylamino, nitro, mercapto, C.sub.1 
-C.sub.3 alkylthio, C.sub.1 -C.sub.3 alkylsulfinyl, C.sub.1 -C.sub.3 
alkylsulfonyl, --NH--C.sub.1 -C.sub.3 alkylsulfonyl, --NC.sub.1 -C.sub.3 
alkyl-C.sub.1 -C.sub.3 alkylsulfonyl, SO.sub.3 H, SO.sub.2 NH.sub.2, 
--CH.sub.2 NH.sub.2,--A.sub.1 -(CH.sub.2).sub.n -Het, --A.sub.1 
--(CH.sub.2).sub.n --(C.sub.1 -C.sub.6 alkyl substituted cyclohexyl), or 
--A.sub.1 --(CH.sub.2).sub.n - cyclohexyl; wherein A.sub.1 is O, or S; 
By "Het" is meant a 5- or 6-membered saturated or unsaturated ring 
containing from one to three heteroatoms selected from the group 
consisting of nitrogen, oxygen, and sulfur, and including any bicyclic 
group in which any of the above heterocyclic rings is fused to a phenyl 
ring; which heterocycle ring is substituted by zero to three of the 
following: C.sub.1 -C.sub.6 alkyl, hydroxy, hydroxy (C.sub.1 -C.sub.5 
alkyl), halogen, amino, amino (C.sub.1 -C.sub.5 alkyl), nitro, mercapto, 
mercapto (C.sub.1 -C.sub.5 alkyl), --SO.sub.3 H, --SO.sub.2 NH.sub.2, 
--O--C.sub.1 -C.sub.5 alkyl, --(CH.sub.2).sub.n - aryl, or 
--(CH.sub.2).sub.n -cyclohexyl; wherein n is zero to five, inclusive. 
The reaction temperature range for the process of the present invention is 
-20.degree. C. to +45.degree. C. The preferred range is +5.degree. to 
+20.degree. C. +15.degree. C. is most preferred. 
Solvents that will work in the process of the present invention include 
methanol, ethanol, i-propanol, acetone, dimethylformamide (DME) and 
tetrahydrofuran (THF); with the proviso that if acetone, DMFF or THF are 
used then a proton source, such as an alcohol, like the ones mentioned 
above, or water must also be present. The amount of such proton source 
required would typically be .gtoreq.1eq., but would be readily apparent to 
one of ordinary skill in the art. Water and tetrahydrofuran are a 
preferred solvent combination. 
Cobalt is the preferred metal ion (Co.sup.+2 or Co.sup.+3). Sources of 
cobalt include CoCl.sub.2 (cobaltous chloride) and Co(OAc).sub.2 
(cobaltous diacetate) or CoCl.sub.3 (cobaltic chloride). 
By "ligand" is meant a complexing agent for a metal ion. In addition to 
dimethylglyoxime, which is the preferred ligand, other ligands that may be 
used are 2, 2'-bipyridyl and 1,10-phenanthroline, which should be used in 
at least a 1:1 mole ratio with the cobalt ion. Most preferred is the 
ligand to cobalt ratio of 50:1. 
Sodium borohydride (NaBH.sub.4) is the preferred reducing agent, but other 
borohydrides, such as lithium borohydride, potassium borohydride, 
tetraalkylammonium borohydride or zinc borohydride may be used. 
By "halo" is meant the halogens: fluorine, chlorine and bormine. 
CHART A 
Chart A illustrates the preparation of pioglitazone hydrochloride using the 
new reduction step of the present invention. 
The compound of formula A-1 is prepared as described in Y. Momose et al., 
Chem. Pharm. Bull., 39:1440 (1991); K. Meguro et al., Japan. Patent 139182 
(1988); and Chem. Abstr., 109:6504h (1988); which are expressly 
incorporated by reference herein. 
The compound of formula A-1 is reduced to the compound of formula A-2 using 
a cobaltous chloride/bidentate ligand/sodium borohydride catalyst system. 
These reactants may be varied, as described above, by one of ordinary 
skill in the art. 
The compound of formula A-2 is converted to the hydrochloride salt of 
formula A-3 by procedures readily known and available to one of ordinary 
skill in the art, including the use of concentrated hydrochloric acid. 
Below are detailed examples illustrating this new reduction method. The 
procedures of Example 3 are most preferred.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention is seen more fully by the examples below. 
EXAMPLE 1 
Reduction Step in the Preparation of Pioglitazone Hydrochloride (Formula 
A-3) Refer to Chart A. 
Part A 
A slurry of 3.544 g of the compound of formula A-1 in 45 ml of water is 
cooled to 3.degree. C. and 0.51 ml of 50% sodium hydroxide is added. The 
resulting solution is then treated with 22 mg of dimethylglyoxime, and 
then 1.0 g of powdered blue indicating silica gel (containing about 0.7 wt 
% CoCl.sub.2), 432 mg of sodium borohydride and 5.0 ml of 
dimethylformamide (DMF) are added in that order. A thin black slurry 
results. The reaction mixture is stirred at about 17.degree. C. for 25 
hours at which time high pressure liquid chromatography (LC) indicates no 
remaining starting material. The silica gel is removed by filtration and 
the flask and solids are rinsed with a little water. The combined flitrate 
and rinse are treated with a solution of 1.90 ml acetic acid in 14ml of 
water in order to precipitate the product. After stirring for 2 hours at 
room temperature, the solids are collected by filtration, rinsed with 
three-14 ml portions of water and vacuum dried at 60.degree. C. overnight 
to provide 3.20 g of crude product of formula A-2. 
Part B 
This product is slurried with 3.2 g of magnesol in 70 nil of ethyl acetate 
for 2 hours at 70.degree. C. This slurry is transferred to a soxlet 
extraction thimble aid the solids are extracted with hot ethyl acetate 
(100 ml) for 5 days. The volume of the product slurry is adjusted to 70 ml 
by distillation and then the temperature is lowered to 50.degree. C. and 
2.2 ml of concentrated hydrochloric acid is added. The resulting slurry of 
the hydrochloric acid (HC 1) salt is stirred at 50.degree. C. for 1 hour 
and then cooled to 0.degree. C. The solids are collected, rinsed with 
three-8 ml portions of room temperature ethyl acetate and dried at 
60.degree. C. overnight to give 3.025 g of the title product. 
EXAMPLE 2 
Reduction Step in the Preparation of Pioglitazone Hydrochloride (Formula 
A-3) Refer to Chart A. 
Part A 
To a 100 ml 3-necked round bottomed flask, equipped with mechanical 
stirrer, is charged 1.772 g of the compound of formula A-1, 25 ml of 
water, 6.0 ml of tetrahydrofuran, and 2.0 ml of 1.0N sodium hydroxide. The 
mixture is stiffed at 25.degree. C. for 10 min. and cooled to 15.degree. 
C. To the cooled mixture is added 0.05-0.50 ml of catalyst solution, 
prepared by dissolving 0.232 g of dimethylglyoxime and 0.012 g of 
cobaltous chloride .cndot.6 H.sub.2 O in 5.0 ml of dimethylformamide, and 
then a solution of 0.378 g of sodium borohydride and 0.5 ml of 1.0N sodium 
hydroxide diluted with 3.5 ml of water is added at a rate of 0.1 ml/min. 
The reaction is stirred at 15.degree. C. for 3 hours and then 2.6 ml of 
acetone is added to quench any remaining sodium borohydfide. After 
stirring for 0.5 hours, the solution is extracted with three 15 ml 
portions of ethyl acetate, and then it is acidified by the dropwise 
addition of 2.3 ml of glacial acetic acid diluted with 5.0 ml of water. 
Upon acidification, the product precipitates as white solids. The slurry 
is cooled to 0.degree. C. and stirred for 0.5 hours prior to filtration. 
The collected product is washed with three 15 ml portions of water and 
dried at 45.degree. C. under vacuum. The yield of crude product of formula 
A-2 is 1.583 g. 
Part B 
The crude product of formula A-2 is converted to the hydrochloride salt 
title product by the method described in Example 1, Part B. 
EXAMPLE 3 
Reduction Step in the Preparation of Piogliazone Hydrochloride (Formula 
A-3) Refer to Chart A. 
Part A 
A slurry of 5.0 g of the compound of formula A-1 in 15 ml of water, 9 ml of 
tetrahydrofuran and 9.5 ml of 1N sodium hydroxide is treated with a 
solution of 42 mg of cobalt (II) chloride .cndot.H.sub.2 O in 4 ml of 1:1 
aqueous tetrahydrofuran. The temperature is adjusted to 15.degree. C. and 
a solution of 667 mg of sodium borohydride in 15 ml of water containing 
1.8 ml of 1N sodium hydroxide is added dropwise while maintaining the 
temperature at 15.degree. C. to 18.degree. C. The reaction mixture is 
quenched with 5.3 ml of acetone and then extracted with ethyl acetate as 
described in Example 2. The aqueous layer containing crude product of 
formula A-2 is acidified to pH 6.5 using 9 ml of 20% aqueous acetic acid. 
The resulting slurry is treated with 25 ml of ethyl acetate and is stirred 
at 70.degree. C. for 2 hours. After cooling the slurry to 15.degree. C., 
the solids are collected, washed first with water and then with methanol 
followed by drying at 65.degree. C. The yield of the product of formula 
A-2 is 4.75 g. 
Part B 
A 5.00 g sample of the above solids is slurried at room temperature in 30 
ml of methanol and then treated with 1.0 equivalent of conc. hydrochloric 
acid in 13 ml of methanol. The slurry is stiffed at 24.degree. C. until 
all of the solids dissolved (2 hours). The solution is concentrated by 
vacuum distillation to 20 ml. The solvent changes over to ethyl acelate by 
displacement vacuum distillation. The desired hydrochloride salt 
precipitates during this solvent exchange. The slurry is cooled to 
2.degree. C. and the solids are collected by vacuum filtration, washed 
with cold ethyl acetate and dried in the vacuum oven at 60.degree. C. The 
pioglitazone hydrochloride salt weighed 5.06 g and showed 97.7% quality by 
LC analysis. 
##STR2##