The present invention provides a simple process for preparation of highly pure pioglitazone or salt thereof. In addition the present invention provides pioglitazone or salt thereof having 0.1% or less of dehydropioglitazone impurity.
Pioglitazone (hereinafter referred to as PGL) of Formula I is chemically, [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl] methyl]-2,4-] thiazolidinedione, used as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM) either alone or in combination with sulphonylureas, metformin or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Commercially pioglitazone is available in form of its monohydrochloride salt.
(Formula Removed)
Several processes are known in the literature for making PGL or salt thereof, viz., US Patent Nos US 4,687,777; US 5,585,495; US 4,812,570; US 5,554,758; US 5,952, 509 and US 6,100,403; US Application Nos US 2002/0106762 and US 2002/0050563; PCT Application Nos WO 03/53367; WO 03/80056; WO 04/07490; WO 04/024059; WO04/101560 and WO 04/101561.
Dehydropioglitazone (hereinafter reffered to as DHP of Formula II) is known as an intermediate in synthesis of pioglitazone or salt thereof.
(Formula Removed)
In addition, DHP is also present as process impurity or degradation product in PGL or salt thereof. Several reasons are attributed for generation of DHP in PGL. Incomplete reduction of DHP, oxidation of PGL during isolation or while on stability are some of the factors responsible for generation of this impurity.
No toxicity data is available in literature on DHP, therefore presence of DHP in qualifying quantities in final PGL or salt thereof is not acceptable by regulatory agencies across the world. It is reported in Chemical & Pharmaceutical Bulletin 39(6). 1440-1445, 1991, that DHP has potent hypoglycemic and hypolipidemic activities comparable to that of PGL, however toxicity data of DHP is not reported in the literature.
Several approaches are used to control the levels of DHP impurity in pioglitazone active substance. Reducing the product with a suitable noble metal catalyst in presence of hydrogen is most commonly applied. However, the cost of such reductive processes is very high.
The present inventors have found that while following Example 1 as provided in US Patent No. 4,687,777 (hereinafter referred to as the '777 Patent) for preparation of PGL or salt thereof, the finished product obtained has more than 0.2%w/w of DHP when measured by HPLC. In our studies, we observed that during the hydrolysis step of pioglitazone imino ether in alcohol and concentrated hydrochloric acid, a blackish shiny mirror deposited on the inner walls of the reaction vessel. This was observed irrespective of the nitrogen atmosphere under which the reaction was usually performed. The formation of metallic copper indicated some redox process in which the undesired process of oxidation of pioglitazone to dehydropioglitazone occurred. Thus, it was noticed that carry over of copper from step b) of Example 1 to step d) of Example 1 is responsible of oxidative degradation of PGL to form DHP. In order to confirm this finding present inventors have refluxed pure PGL having 0.17% w/w of DHP with little quantity of cuprous bromide in ethanol for few hours. The product obtained has about 0.96% w/w of DHP as an impurity. Thus in presence of copper about seven six fold increase in DHP impurity was noticed.
Possibly the simple water washings of the organic layer containing crude pioglitazone bromo ether were not effective in removing all traces of copper salts. Therefore, it was reasoned that there was a need for use of some copper chelating agents that can bind to copper salts and remove them more effectively.
The present inventors in order to prevent the carry over of copper from step b) of Example 1 have washed the reaction mass after completion of step b) with a chelating agent, for example, EDTA, for removal of copper by complex formation. The so obtained product is further subjected to reaction sequence to step d). PGL obtained as a product has less than 0.1% w/w of DHP as impurity when measured by HPLC. A similar result is observed when product of step c) of Example 1 of the '777 Patent is washed with a chelating agent.
A first aspect of the present invention provides a process for preparation of PGL or salt thereof wherein the said process comprises of,
a) reacting PGL amino ether of Formula III,
(Formula Removed)
with alkyl acrylate of Formula IV, wherein R is C1-4 alkyl group
(Formula Removed)
in presence of sodium nitrite, cuprous salt and hydrobromic acid,
b) washing the reaction mass with a chelating agent to remove copper,
c) condensing the product PGL bromo ether of Formula V,
(Formula Removed)
with thiourea to get PGL imino ether of Formula VI,
(Formula Removed)
d) hydrolyzing PGL imino ether of Formula VI to PGL or salt thereof.
PGL amino ether of Formula III is dissolved in a mixture of organic solvents such as ketones and alkanol and under cooling aqueous hydrobromic acid is added. The mixture is further cooled and to it is added a solution of sodium nitrite in water followed by addition of alkyl acrylate such as methyl acrylate in one lot under cooling. The temperature is raised to about 35°C and cuprous oxide is added in small portions. After completion of reaction the solvent is recovered under vacuum and the residue is extracted with chlorinated hydrocarbon or aromatic hydrocarbon solvent and washed with water. The organic layer is washed with solution of chelating agent followed by water followed by evaporation of organic solvent to get crude PGL bromo ether of Formula V.
The chelating agents are known to a person of ordinary skills in the art and include ethylenediaminetetraacetic acid (EDTA) or salt thereof, bidentate, tridentate ligands and the like.
The crude PGL bromo ether of Formula V is refluxed with thiourea in presence of an alkanol and sodium acetate. After completion of reaction the solvent is evaporated and the residue is triturated with second organic solvent selected from the group comprising of diethyl ether, diisopropyl ether, cyclohexane, methyl t-butyl ether and the like to precipitate the PGL imino ether of Formula VI which can be further slurried with second organic solvent and dried.
PGL imino ether is then hydrolyzed in presence of an aqueous acid optionally under nitrogen atmosphere in presence of an alkanol. After completion of reaction the reaction mass is neutralized using a base and chilled to precipitate PGL which can then be suitably converted to its salt by treating with an acid or base as per the processes known in the art. The HPLC analysis of this crude PGL shows less than 0.1% w/w of DHP impurity.
A second aspect of the present invention provides a process for preparation of PGL or salt thereof wherein the said process comprises of, a) reacting PGL amino ether of Formula III,
(Formula Removed)
with alkyl acrylate of Formula IV, wherein R is C1-4 alkyl group
(Formula Removed)
in presence of sodium nitrite, cuprous salt and hydrobromic acid,
b) condensing the product PGL bromo ether of Formula V,
(Formula Removed)
with thiourea to get PGL imino ether of Formula VI,
(Formula Removed)
c) washing the reaction mass with a chelating agent to remove copper,
d) hydrolyzing PGL imino ether of Formula VI to PGL or salt thereof.
The process of this aspect is similar to the process of first aspect except that instead of washing the solution PGL bromo ether in organic solvent with a chelating agent, in this aspect solution of PGL imino ether in organic solvent is washed with a suitable chelating agent. HPLC analysis of this PGL obtained as per this aspect of the invention shows less than 0.1% w/w of DHP impurity.
A third aspect of the present invention provides a process for preparation of PGL or salt thereof having less than 0.1% w/w DHP as impurity wherein the said process comprises of,
washing the solution of PGL bromo ether of Formula V in organic solvent with a solution of chelating agent.
A fourth aspect of the present invention provides a process for preparation of PGL or salt thereof having less than 0.1% w/w DHP as impurity wherein the said process comprises of, washing the solution of PGL imino ether of Formula VI in organic solvent with a solution of chelating agent.
A fifth aspect of the present invention provides PGL or salt thereof having less than 0.1% w/w DHP as impurity. Preferably PGL or salt thereof of the present invention has less than 0.05% w/w DHP as impurity.
A sixth aspect of the present invention provides PGL bromo ether of Formula V and PGL imino ether of Formula VI having less than 20 ppm of copper content when determined by ICP-MS technique. It was observed that when the solution of compound of either Formula V or VI is washed with chelating agent the residual copper content was reduced to less than 20 ppm when determined by ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy) technique. It was also observed that when such a low content of copper is present in these intermediates the resulting PGL obtained has less than 0.1% w/w of DHP as impurity.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
REFERENCE EXAMPLE 1 PGL PREPARED AS PER THE EXAMPLE 1 OF THE '777 PATENT
a) Preparation of PGL bromo ether: Pioglitazone amino ether (60 g) was dissolved in a mixture of acetone (150 ml) and methanol (60 ml). After cooling to about 10°C, aqueous hydrobromic acid (120 ml) was added in 30 minutes during which process rise in temperature from 10 to 30°C was noticed. The mixture was cooled to 0-5°C and a solution of sodium
nitrite (20 g in 48 ml water) was added over 30 minutes. To the resultant mass was added methyl acrylate (135 ml) in one lot. The temperature is increased to 35°C and cuprous oxide (2.4 g) was added in small portions over 15 minutes keeping the temperature between 35 and 40°C. After stirring the mixture at 35-42°C for 2 hours, the solvent was recovered under vacuum and to the residue was added dichloromethane (240 ml) and water (240 ml) and the biphasic mixture was stirred and then allowed to settle. After separating the layers, the aqueous layer was extracted with dichloromethane (120 ml). The organic layers containing PGL bromo ether were combined and washed with water (2 x 180 ml). Dichloromethane layer was concentrated completely under vacuum to get crude PGL bromo ether Yield: 87 g. Copper Content: 14000 ppm by ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy)
b) Preparation of PGL imino ether: The crude PGL bromo ether (87 g) was dissolved in
denatured spirit (315 ml) and sodium acetate trihydrate (63 g) and thiourea (19 g) was added
at 30-32°C. The mixture was then refluxed at 80°C for 3-4 hours. After completion of
reaction the solvent was recovered under vacuum and the residue was triturated with
diisopropyl ether and water, neutralized and filtered. The solid was slurry washed with
diisopropyl ether and then dried in air at 30°C for 18 hours to get crude PGL imino ether.
Yield: 70 g.
Copper Content: 10950 ppm by ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy)
c) Preparation of PGL: The crude PGL imino ether (70 g) is taken in denatured spirit (500
ml) and concentrated hydrochloric acid (51 ml) was added to it while stirring under nitrogen
atmosphere. The mixture thus obtained was stirred at 79-80°C for 18 hours. After completion
of reaction the mass was cooled to 30°C and neutralized using triethylamine (56 ml) at 10°C
and allowed to stir for 1 hour at 5-10 °C. The product is filtered cold, slurry washed and dried
at 45-50°C for 6 hours to get crude PGL.
Yield: 38 g
DHP impurity: 0.32% w/w by HPLC analysis.
Copper Content: 4400 ppm by ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy)
EXAMPLE 1
PREPARATION OF PGL HAVING LESS THAN 0.1% WAV DHP IMPURITY
a) Preparation of PGL bromo ether: Pioglitazone amino ether (60 g) was dissolved in a
mixture of acetone (150 ml) and methanol (60 ml). After cooling to about 10°C, aqueous
hydrobromic acid (120 ml) was added in 30 minutes during which process rise in temperature
from 10 to 30°C was noticed. The mixture was cooled to 0-5°C and a solution of sodium
nitrite (20 g in 48 ml water) was added over 30 minutes. To the resultant mass was added
methyl acrylate (135 ml) in one lot. The temperature is increased to 35°C and cuprous oxide
(2.4 g) was added in small portions over 15 minutes keeping the temperature between 35 and
40°C. After stirring the mixture at 35-42°C for 2 hours, the solvent was recovered under
vacuum and to the residue was added dichloromethane (240 ml) and water (240 ml) and the
biphasic mixture was stirred and then allowed to settle. After separating the layers, the
aqueous layer was extracted with dichloromethane (120 ml). The organic layers containing
PGL bromo ether were combined and washed with water (2 x 180 ml). The dichloromethane
layer was further washed with dilute solution of ethylenediamine-tetra-acetic acid disodium
salt (2 x 240 ml of 2% aqueous solution) followed by water (180 ml). The organic layer was
concentrated under vacuum to provide crude pioglitazone bromo ether.
Yield: 87 g.
Copper Content: Less than 20 ppm by ICP-MS (Inductively Coupled Plasma - Mass
Spectroscopy)
b) Preparation of PGL imino ether: The crude PGL bromo ether (87 g) was dissolved in
denatured spirit (315 ml) and sodium acetate trihydrate (63 g) and thiourea (19 g) was added
at 30-32°C. The mixture was then refluxed at 80°C for 3-4 hours. After completion of
reaction the solvent was recovered under vacuum and the residue was triturated with
diisopropyl ether and water, neutralized and filtered. The solid was slurry washed with
diisopropyl ether and then dried in air at 30°C for 18 hours to get crude PGL imino ether.
Yield: 70 g.
Copper Content: Less than 20 ppm by ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy)
c) Preparation of PGL: The crude PGL imino ether (70 g) is taken in denatured spirit (500
ml) and concentrated hydrochloric acid (51 ml) was added to it while stirring under nitrogen
atmosphere. The mixture thus obtained was stirred at 79-80°C for 18 hours. After completion
of reaction the mass was cooled to 30°C and neutralized using triethylamine (56 ml) at 10°C
and allowed to stir for 1 hour at 5-10 °C. The product is filtered cold, slurry washed and dried
at 45-50°C for 6 hours to get crude PGL.
Yield: 38 g
DHP impurity: 0.04% w/w by HPLC analysis.
Copper Content: Less than 20 ppm by ICP-MS (Inductively Coupled Plasma - Mass
Spectroscopy)
EXAMPLE 2
PREPARATION OF PGL HAVING LESS THAN 0.1% WAV DHP IMPURITY
a) Preparation of PGL bromo ether: Pioglitazone amino ether (60 g) was dissolved in a
mixture of acetone (150 ml) and methanol (60 ml). After cooling to about 10°C, aqueous
hydrobromic acid (120 ml) was added in 30 minutes during which process rise in temperature
from 10 to 30°C was noticed. The mixture was cooled to 0-5°C and a solution of sodium
nitrite (20 g in 48 ml water) was added over 30 minutes. To the resultant mass was added
methyl acrylate (135 ml) in one lot. The temperature is increased to 35°C and cuprous oxide
(2.4 g) was added in small portions over 15 minutes keeping the temperature between 35 and
40°C. After stirring the mixture at 35-42°C for 2 hours, the solvent was recovered under
vacuum and to the residue was added dichloromethane (240 ml) and water (240 ml) and the
biphasic mixture was stirred and then allowed to settle. After separating the layers, the
aqueous layer was extracted with dichloromethane (120 ml). The organic layers containing
PGL bromo ether were combined and washed with water (2 x 180 ml). Dichloromethane
layer was concentrated completely under vacuum to get crude PGL bromo ether
Yield: 87 g.
b) Preparation of PGL imino ether: The crude PGL bromo ether (87 g) was dissolved in
denatured spirit (315 ml) and sodium acetate trihydrate (63 g) and thiourea (19 g) was added
at 30-32°C. The mixture was then refluxed at 80°C for 3-4 hours. After completion of
reaction the solvent was recovered under vacuum and the residue was triturated with diisopropyl ether and water, neutralized and filtered. The solid was slurry washed with diisopropyl ether and then dried in air at 30°C for 18 hours to get crude PGL imino ether. The crude product obtained was dissolved in dichloromethane (240 ml) and the organic layer was washed with dilute solution of ethylenediamine-tetra-acetic acid disodium salt (2 x 240 ml of 2% aqueous solution) followed by water (180 ml). The organic layer was concentrated under vacuum to provide crude pioglitazone imino ether. Yield: 70 g.
Copper Content: Less than 20 ppm by ICP-MS (Inductively Coupled Plasma - Mass Spectroscopy)
c) Preparation of PGL: The crude PGL imino ether (70 g) is taken in denatured spirit (500
ml) and concentrated hydrochloric acid (51 ml) was added to it while stirring under nitrogen
atmosphere. The mixture thus obtained was stirred at 79-80°C for 18 hours. After completion
of reaction the mass was cooled to 30°C and neutralized using triethylamine (56 ml) at 10°C
and allowed to stir for 1 hour at 5-10 °C. The product is filtered cold, slurry washed and dried
at 45-50°C for 6 hours to get crude PGL.
Yield: 38 g
DHP impurity: 0.087% w/w by HPLC analysis.
Copper Content: Less than 20 ppm by ICP-MS (Inductively Coupled Plasma - Mass
Spectroscopy)

WE CLAIM:
1. A process for preparation of PGL or salt thereof wherein the said process comprises of,
a) reacting PGL amino ether of Formula III,
(Formula Removed)
with alkyl acrylate of Formula IV, wherein R is C1-4 alkyl
(Formula Removed)
in presence of sodium nitrite, cuprous salt and hydrobromic acid,
b) washing the reaction mass with a chelating agent to remove copper,
c) condensing the product PGL bromo ether of Formula V,
(Formula Removed)
with thiourea to get PGL imino ether of Formula VI,
(Formula Removed)
d) hydrolyzing PGL imino ether of Formula VI to PGL or salt thereof.
2. A process according to claim 1 wherein alkyl acrylate is methyl acrylate.
3. A process according to claim 1 wherein chelating agent is ethylenediaminetetraacetic acid
(EDTA) or salt thereof.
4. A process according to claim 1 wherein step d) hydrolysis is carried out in aqueous
hydrochloric acid.
5. A process for preparation of PGL or salt thereof wherein the said process comprises of,
a) reacting PGL amino ether of Formula III,
(Formula Removed)
with alkyl acrylate of Formula IV, wherein R is C1-4 alkyl group
(Formula Removed)
in presence of sodium nitrite, cuprous salt and hydrobromic acid,
b) condensing the product PGL bromo ether of Formula V,
(Formula Removed)
with thiourea to get PGL imino ether of Formula VI,
(Formula Removed)
c) washing the reaction mass with a chelating agent to remove copper,
d) hydrolyzing PGL imino ether of Formula VI to PGL or salt thereof.
6. A process according to claim 5 wherein chelating agent is ethylenediaminetetraacetic acid
(EDTA) or salt thereof.
7. A process for preparation of PGL or salt thereof having less than 0.1% w/w DHP as
impurity wherein the said process comprises of, washing the solution of PGL bromo ether
of Formula V in organic solvent with a solution of chelating agent.
(Formula Removed)
8. A process for preparation of PGL or salt thereof having less than 0.1% w/w DHP as
impurity wherein the said process comprises of, washing the solution of PGL imino ether
of Formula VI in organic solvent with a solution of chelating agent.
(Formula Removed)
9. PGL or salt thereof having less than 0.1% w/w DHP as impurity.
10. PGL bromo ether of Formula V and PGL imino ether of Formula VI having less than 20
ppm of copper content when determined by IPC-MS technique.