This patent application claims priority from Indian Patent Application bearing number 1192/CHE/2009 dated May 25, 2009.

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Rosiglitazone free base. The present invention also relates to a process for the preparation of Rosiglitazone malonate. The present invention further relates to a process for the preparation of pure Rosiglitazone free base from its malonate salt.

BACK GROUND OF THE INVENTION:

Diabetes mellitus is a complex, chronically, progressive disease, which can eventually adversely affect the functioning of the kidneys, eyes, nervous and vascular systems. Most individuals diagnosed with diabetes mellitus show symptoms for non insulin dependent diabetes mellitus (NIDDM) that is, Type II diabetes. Type II diabetes is a debilitating disease that arises from improper energy storage and utilization. Type II diabetes is defined by high plasma glucose levels and is characterized by both peripheral insulin resistance and insufficient insulin secretion by the p-cells of the pancreas. The current approach for handling hyperglycemia is to alleviate insulin resistance rather than to stimulate insulin secretion. The thiazolidinedione class of antidiabetics such as pioglitazone, englitazone, troglitazone and ciglitazone has been shown to alleviate insulin resistance in humans.

Rosiglitazone, also known as 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine -2,4-dione is represented by chemical formula-l:

Formula-I Rosiglitazone is a member of thiazolidinedione class and is one of the most potent compounds of this class. Since, Rosiglitazone is the preferred drug for non-insulin dependent diabetes mellitus, hence, the process for its production, yield obtained and costs involved are all constantly being critically surveyed for optimization.

Chemical synthesis of Rosiglitazone was first disclosed in EP patent no. 306228. Rosiglitazone of formula-l is usually prepared by the reduction of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzylidine]-thiazolidine-2,4-dione of formula-ll as shown in the reaction given below. The reduction of the compound of formula-ll to Rosiglitazone of formula-l may be carried out by various methods.

Catalytic hydrogenation of the compound of formula-ll was first disclosed in EP 306228. The reaction was carried out in 1,4-dioxane in the presence of 10% palladium on carbon. However, there was a high consumption of the very expensive catalyst, about 150% (w/w) based on the weight of the substance of formula-ll being used. Besides the excessive consumption of the catalyst, a high consumption of the solvent, caused by low solubility of the substance undergoing reduction in 1,4-dioxane, presents another disadvantage of this method.

EP 1786808 disclosed a method for the preparation of Rosiglitazone of formula-l by reduction of compound of formula-ll using atleast one borohydride of general formula MBH4, wherein M stands for a cation from the group of Na, Li, K, Zn and R4N, and R stands for a C1-C5 alkyl group, in the presence of cobalt salts and at least one complexing agent, base and a suitable solvent. The product was isolated from the reaction mixture, after pH adjustment to 5 by adding a diluted acid, followed by the addition of 10% aqueous solution of sodium hydrogen carbonate into the reaction mixture, filtering the precipitated product and finally crystallizing the crude Rosiglitazone. The described method usually leads with 70 to 90% yields to a free base of Rosiglitazone of formula-l.

IN patent no. 192995 disclosed the reduction of formula-ll to compound of formula-l using sodium borohydride in the presence of cobalt chloride hexahydrate, dimethyl glyoxime in methanol and sodium hydroxide or potassium hydroxide as a base. The product wasisolated from the reaction mixture, after pH adjustment to 4 to 7 (using acetic acid), followed by extraction using methylene chloride, evaporation of solvent to give crude product and finally purified using isopropyl alcohol.

PCT application WO 9923095 has described possibilities to carry out the catalytic hydrogenation in mediums other than the initially used dioxane, e.g. in acetic acid and its mixtures with water, in alcohols, mineral acids, and in mixtures of these solvents. The reduction was carried out in the presence of 10% palladium on carbon at higher temperatures 80 to 115°C and under the pressure of hydrogen of above 20psi. The catalyst consumption was lower in comparison with the aforementioned method, yet it was still very high (5 to 100 %, preferably 25 to 50 %, based on the weight of the substance of formula-ll. The product was obtained after filtration and evaporation of the solvent with a yield of 70 to 80%.

A similar method of the reduction was described in patent application WO 03/053367 wherein catalytic hydrogenation of analogous substrates was carried out in formic acid in the presence of 10% palladium on carbon at pressures of 0.2 to 0.6 MPa with yields over 80 %.

Another method for the preparation of formula-l was published in patent application WO9837073. The reduction of the compound of formula-ll was carried out using complex lithium borohydrides such as LiB(sec-Bu)3H, LiBH4, NaBH4 in a mixture with LiCI in the presence of pyridine in tetrahydrofuran.

A method for the reduction of compound of formula-ll using magnesium turnings in boiling methanol was published in J.Med.Chem. 37, 3977 (1994). The product was isolated from the reaction mixture, after pH adjustment to 7.5 to 8 (using dil. HCI), followed by extraction using dichloromethane, evaporation of solvent to give crude product and finally purified using chromatography (Si02, 2% methanol in dichloromethane). The yield of the product was, however, only 62 %.

Reduction of the double bond in benzylidene of formula-ll was also carried out biochemically using yeasts of the genus Rhodotorula. The operation of the biochemical conversion under different conditions (type of buffer, pH, yeast species) influences both the conversion itself
and the ratio of the enantiomers of the final substance. The synthesis was published in patent US 5,726,055 and in journal J.Chem.Soc. Perkin Trans. 1, 3319 (1994). Thus there is need for an alternate, more convenient, improved process for producing Rosiglitazone and its pharmaceutical acceptable salts on industrial scale.

OBJECT OF THE INVENTION:

The main object of the present invention is to provide an improved process for the preparation of Rosiglitazone.

Another object of the present invention is to provide a process for the preparation of Rosiglitazone malonate.

Yet another object of the present invention is to provide a process for the preparation of Rosiglitazone free base from its malonate salt.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparation of Rosiglitazone free base of formula-l by reduction of compound of formula-ll using metal borohydrides in the presence of solvent, cobalt salt, ligand and in the absence of a base to yield Rosiglitazone free base of formula-l.

Another aspect of the present invention is to provide a process for preparation of pure Rosiglitazone free base by reduction of compound of formula-ll using metal borohydrides in the presence of solvent, cobalt salt, ligand and in the absence of a base to yield Rosiglitazone free base of formula-l, converting the compound of formula-l into malonate salt, neutralizing the malonate salt and isolating pure Rosiglitazone free base.

Yet another aspect of the present invention is to provide a process for the preparation of Rosiglitazone malonate by reacting Rosiglitazone base with malonic acid in a solvent at a reflux temperature, cooling the solution and isolating the Rosiglitazone malonate salt.

Another aspect of the present invention is to provide a process for the preparation of pure Rosiglitazone free base from its maionate salt by neutralizing malonic acid salt with a base and isolating pure Rosiglitazone free base.
The stepwise process is shown in the scheme given below:

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses an improved process for the preparation of Rosiglitazone or its maionate salt thereof comprising reduction of benzylidine intermediate with metal borohydride in the presence of cobalt salt and a ligand to yield Rosiglitazone free base which is further purified through maionate salt.

One embodiment of the present invention provides an improved process for the preparation of Rosiglitazone free base of formula-l,
which comprising the steps of:

a) reducing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazoliclinone
compound of formula-ll

Formula-ll in the presence of solvent, reducing agent, cobalt salt, ligand and in absence of a base,

b) removing the solvent,

c) dissolving the product obtained in step b) in a solvent,

d) adjusting the pH with an acid, and

e) isolating Rosiglitazone free base.
According to the present invention compound of formula-ll is dissolved in solvent and mixture of cobalt salt and a ligand in a solvent were added at ambient temperature. To this mixture reducing agent in a solvent is added slowly in 5-7 equal lots at the same temperature and stirred for about 2-3 hrs. After the completion of the reaction, solvent is removed and the obtained residue is dissolved in another solvent. The pH of the solution is adjusted to 6-7 with an acid at ambient temperature and Rosiglitazone free base of formula-l is isolated.

According to the present invention the cobalt salt is cobalt chloride hexahydrate, ligand is dimethyl glyoxime and the reducing agent is selected from metal borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride. The solvent used for the reaction is selected from methanol, ethanol, propanol, butanol, acetone, methylethylketone, methylisobutyl ketone, acetonitrile, ethyl acetate, water or mixtures thereof. The solvent used for dissolution of residue is selected from ethylacetate, methylethylketone, methylisobutyl ketone or mixtures thereof and acid used for adjusting the pH is selected from acetic acid and hydrochloric acid.

Removal of the solvent may be by distillation, evaporation or filtration. Rosiglitazone free base of formula-l is isolated by filtration.

Another embodiment of the present invention provides an improved process for the preparation of pure Rosiglitazone free base,
which comprises the steps of:

a) reducing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone of compound of formula-ll in the presence of a solvent, reducing agent, cobalt salt, ligand and in the absence of a base,

b) removing the solvent,

c) dissolving the product obtained in step b) in a solvent

d) adjusting the pH with an acid to get Rosiglitazone free base of formula-l,
Formula-I

e) reacting the compound of formula-l with malonic acid in solvent to get Rosiglitazone malonate salt,

f) neutralizing malonate salt obtained in step c) with a base, and

g) isolating pure Rosiglitazone free base.
According to the present invention compound of formula-ll is dissolved in solvent and mixture of cobalt salt and a ligand in a solvent were added at ambient temperature. To this mixture reducing agent in a solvent is added slowly in 5-7 equal lots at the same temperature and stirred for about 2-3 hrs. After the completion of the reaction, solvent is removed and the obtained residue is dissolved in another solvent. The pH of the solution is adjusted to 6-7 with an acid at ambient temperature to get Rosiglitazone free base of formula-l. The compound of formula-l is treated with malonic acid in a solvent at reflux temperature to form a clear solution then cooled to room temperature and stirred for about 1-2 hrs to get malonate salt of the same.

Rosiglitazone malonate thus obtained is treated with a base in a solvent to get pure Rosiglitazone free base.

According to the present invention cobalt salt is cobalt chloride hexahydrate, ligand is dimethyl glyoxime and the reducing agent is selected from metal borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride. The solvent used for the reaction is selected from methanol, ethanol, propanol, butanol, acetone, methylethylketone, methylisobutyl ketone, acetonitrile, ethyl acetate, water or mixtures thereof. The solvent used for dissolution of residue is selected from ethylacetate, methylethylketone, methylisobutyl ketone or mixtures thereof and acid used for adjusting the pH is selected from acetic acid and hydrochloric acid.

According the present invention the solvent used in step e) is selected from ethylacetate, methylethylketone, methylisobutyl ketone or mixtures thereof. The base used for neutralization is selected from sodium hydroxide or sodium carbonate. Compound of formula-l is isolated in a solvent selected from ketonic solvent such as acetone, butanone, methyethylketone, methylisobutylketone, alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol or mixtures thereof.

Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Rosiglitazone malonate, comprises the steps of:

a) reacting Rosiglitazone free base of formula-l with malonic acid in a solvent at reflux temperature,

b) cooling the solution, and

c) isolating the Rosiglitazone malonate.
According to the present invention Rosiglitazone free base of formula-l is reacted with malonic acid in a solvent at reflux temperature to form a clear solution. The solution is then cooled to room temperature and stirred for about 1-2 hrs thus isolating Rosiglitazone malonate. The solvent used is acetone and Rosiglitazone malonate is isolated by filtration.

Yet another embodiment of the present invention is to provide a process for the preparation of pure Rosiglitazone free base from its malonate salt, comprises the steps of:

a) neutralizing malonic acid salt of Rosiglitazone with a base, and

b) isolating pure Rosiglitazone free base.
According to the present invention, malonate salt of Rosiglitazone is dissolved in a solvent and a base is added at ambient temperature. The reaction mass was heated to about 60-90°C and stirred for about 30 min. Cooled the reaction mass to ambient temperature and isolated pure Rosiglitazone free base.

According to the present invention base used for neutralization is selected from sodium hydroxide or sodium carbonate and the solvents used in the reaction are selected from ketonic solvent such as acetone, butanone, methyethylketone, methylisobutylketone, alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol or mixtures thereof. Pure Rosiglitazone free base is isolated by filtration.

The following non-limiting examples illustrate specific embodiments of the present invention. They should not construe it as limiting the scope of present invention in any way.
Example-1: 4-[2-(N-methyl-N-(2-pyridyl)aminoethoxy]benzaldehyde.

A mixture of toluene (2L), potassium hydroxide (73.6g) and 18-Crown-6 (15g) were heated to reflux and removed water azeotropically by using dean stark apparatus. The reaction mass was cooled to 70-75°C and 2-(N-methyl-N-(2-pyridyl)amino)ethanol (100g) was added. The resulting mixture was stirred at 70-75°C for about 15 min and 4-fluoro benzaldehyde was added to the reaction mixture at same temperature for about 3-4 hrs. The reaction mixture was stirred for about 10 hours at 70-75°C, cooled to 40-50°C and toluene (800ml) was distilled off under reduced pressure. The reaction mixture was cooled to 15-20°C and water (800ml) was added, the pH of the reaction mixture was adjusted to 1-1.5 with hydrochloricacid. The aqueous layer was separated and extracted aqueous layer with toluene (200ml). Toluene was separated and toluene (800ml) was added to aqueous layer. The pH of the aqueous layer was adjusted to 10-11 with sodium hydroxide solution. The organic layer was separated and extracted aqueous layer with toluene (400ml). Total organic layers, were combined heated to reflux and removed water azeotropically by using dean stark apparatus and proceed for next stage without isolation of product.

Example-2: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-
thiazolidinone (Formula-ll).

Toluene layer obtained in example-1 was cooled and a mixture of 2,4-thiazolidenedione (120g), piperidine (3.4g) in acetic acid (3g) and toluene (20ml) was added. The resulting reaction mixture was heated to reflux, maintained at the reflux temperature for about 300-480 min and removed water azeotropically by using dean stark apparatus which is formed in reaction during the maintenance. The reaction mass was cooled to 25-30°C and stirred for about 120 min. The obtained solid was filtered and washed with toluene (100ml). Resultant solid obtained is dried under vacuum at 55-65°C to obtain (170g) of title product.

Example-3: Purification of 5-[4-[2-(Methyl-pyridin-2-yl-amino)-ethoxy]-benzylidene]-thiazolidine-2-dione (Formula-ll).

Crude solid (170g) obtained in example-2 was dissolved in methanol (1020ml) at reflux, cooled to 20-25°C and stir for about 60 min. Solid obtained was filtered, washed with methanol (170 ml) and dried under vacuum at 50-60°C to obtain 140 gm of pure product, HPLC Purity NLT 99%.
Example-4: Rosiglitazone free base of Formula-I from Formula-ll.

To the mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone (100g), methanol (300ml) and DM water (300ml) was added complex of CoCI2/DMG (0.88g/4.32g) in methanol (80ml) at 25-30°C in lots. Sodium borohydride solution in DM water (8.56g in 80ml) was slowly added to the reaction mass in lots and stirred for about 5-8 hrs. The solid obtained was filtered and washed the solid with the mixture of water and methanol in 1:1 (100ml). To the wet solid thus obtained was added mixture of methyl isobutyl ketone (500ml) and DM water (200ml). The pH of the reaction mass was adjusted using acetic acid (25.3g) and heated the mixture to 80-85°C. The organic layer was separated and activated carbon (10g) was added. The reaction mixture was filtered through celite bed and washed with methyl isobutyl ketone (100ml). Filtrate was cooled to 20-25°C and stirred for about 120-180min. The solid obtained was filtered, washed with methylisobutyl ketone (100ml) and dried the solid under vacuum to give 70-80g of the title compound.

Example-5: Rosiglitazone free base of Formula-I from Formula-ll.

To the mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone (10g), methanol (30ml) and DM water (30ml) was added complex of CoCI2/DMG (0.51g/2.1g) in methanol (1.94g) at 25-30°C in 2-5 equal lots.

Sodium borohydride solution in DM water (3.2g) was slowly added to the reaction mass for about 90-120 min in 2-5 equal lots and maintained at the same temperature for about 5-8 hrs. Methanol was distilled out completely under vacuum and methyl isobutyl ketone (70ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 6-7 with dil HCI, heated the mixture to 65-70°C and maintained at the same temperature for about 30 min. The organic layer was separated, washed with 20% sodium chloride solution (20ml) and carbon (1g) was added to the reaction mass, filtered through celite bed, washed the celite bed with methyl isobutyl ketone (10ml) and cooled the solution to 25-30°C for about 120-180 min. The obtained solid was filtered, washed with methyl isobutyl ketone (200ml) and dried the solid under vacuum at 60-65°C to yield 7-8g of the title compound.

Example-6: Rosiglitazone free base of Formula-I from Formula-ll.

To the mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone (10g), methanol (30ml) and DM water (30ml) was added aqueous ammonia solution (4g). The resultant mixture was cooled to 5-10°C and CoCI2/DMG (0.34g/1.6g) in methanol (30ml) was added. Sodium borohydride solution in DM water (3.2g) was slowly added to the reaction mass for about 90-120 min at the same temperature and maintained the reaction mass for about 20-24hrs.

Methanol was distilled completely under vacuum and methyl isobutyl ketone (70ml) was added to the reaction mass. The pH of the reaction mass was adjusted to 5-6 with dil HCI, heated the mixture to 65-70°C and maintained at the same temperature for about 30 min. The organic layer was separated, washed with 20% sodium chloride solution (20ml) and activated carbon (1g) was added to the reaction mixture, filtered through celite bed, washed the celite bed with methyl isobutyl ketone (10ml) and cooled the solution to 25-30°C for about 120-180 min. The obtained solid was filtered, washed with methyl isobutyl ketone (200ml) and dried the solid under vacuum

at 60-65°C to yield 7-8g of the title compound.
Example-7: Rosiglitazone malonate from Rosiglitazone free base of Formula-I.

10 g of Rosiglitazone base and Malonic acid (2.9g) were suspended in acetone (100 ml) at 50-60°C to form a clear solution and stirred for 15-30 min. The hot solution was filtered through hyflow to remove any undissolved particulate.

The resulting clear filtrate was then cooled to 25-30°C and stirred for 1 hr. The solid obtained was filtered, washed with acetone (20 ml) and dried under vacuum at 50°C for 5hr. The product obtained was identified as crystalline Rosiglitazone Malonate.

Example-8: Rosiglitazone malonate from compound of Formula-ll.

To the mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone (100g), methanol (300ml) and DM water (300ml) was added complex of CoCI2 hexahydrate/DMG (4.4g/21.6g) in methanol (400ml) at 25-30°C in lots. Sodium borohydride solution in DM water (7.13g in 66ml) was slowly added in six equal lots to the reaction mass and stirred for about 2 hrs. The reaction mixture was heated for about 20 min and distilled out methanol completely under vacuum. The pH of the reaction mixture was adjusted with dil aqueous HCI (~280ml) and stirred the reaction mixture for about 30-45 min. Methyl isobutyl ketone (800ml) was added to the residue, heated the reaction mass to 70-80°C for about 20-30 min and stirred the reaction mixture for about 30min. The organic layer was separated and activated carbon (10g) was added. The reaction mixture was stirred for about 30-45 min, filtered the activated carbon through hyflow bed and washed with methyl isobutyl ketone (100ml). Malonic acid 23.3g was added to the filtrate and heated the reaction mass to 70-80°C. The reaction mass was cooled to 10-15°C for about 3-4 hrs, filtered the solid, washed the solid with methyl isobutyl ketone (100ml) and dried the solid under vacuum to give 80-100g of the title compound.

Example-9: Rosiglitazone free base of Formula-I from Rosiglitazone malonate.

To the mixture of 100g of Rosiglitazone malonate and DM water (450ml),Sodium hydroxide solution (NaOH 15.5g in DM water 50ml) (65ml) was added at 20-25 °C. The reaction mixture was stirred for about 20 min, methyl isobutyl ketone (800ml) was added and heated the reaction mass to 70-80°C for about 20-30 min. The reaction mixture was stirred for about 30 min, separated the organic layer, filtered the hot solution through micron filter and washed with methyl isobutyl ketone (100ml). The reaction mass was cooled to 20-25°C for about 2-3hrs, filtered the solid, washed the solid with methyl isobutyl ketone (100ml) and dried the solid under vacuum to give 60-75g of the title compound.

Example-10: Purification of Rosiglitazone free base.

Mixture of Rosiglitazone free base as prepared according to example-9 (10g) and methanol (440ml) were heated to 60-65°C for about 15-20 min to get a clear solution. The solution thus obtained was filtered through micron filter and washed with methanol (10ml). Again the mixture was heated to 60-65°C and distilled out methanol completely at atmospheric pressure. The reaction mass was cooled to 25-30°C for about 1-2 hrs. The obtained solid was filtered, washed with methanol (10ml) and dried the solid at 50-55°C under vacuum till LOD content is NMT 0.2% to yield 7-8 g of the title compound.

We Claim:

1. An improved process for the preparation of Rosiglitazone free base of formula-l,
which comprises the steps of:

a) reducing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone compound of formula-ll in the presence of a solvent, reducing agent, cobalt salt, ligand and in the absence of a base,

b) adjusting the pH with an acid, and

c) isolating Rosiglitazone free base of formula-l.

2. An improved process for the preparation of pure Rosiglitazone free base, Pure Rosiglitazone which comprises the steps of:

h) reducing 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidine]-2,4-thiazolidinone of compound of formula-ll in the presence of a solvent, reducing agent, cobalt salt, ligand and in the absence of a base,

i) adjusting the pH with an acid to get Rosiglitazone free base of formula-l,

j) reacting the compound of formula-l with malonic acid in solvent to get Rosiglitazone malonate salt,Rosiglitazone Malonate

k) neutralizing malonate salt obtained in step c) with a base, and

I) isolating pure Rosiglitazone free base.

3. A process for the preparation of pure Rosiglitazone free base comprises the steps
of:

a) neutralizing malonic acid salt of Rosiglitazone with a base, and

b) isolating pure Rosiglitazone free base.

4. The process according to claim land 2, wherein said reducing agent used in step a) is selected from metal borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride.

5. The process according to claim 1 and 2, wherein said cobalt salt used in step a) is cobalt chloride hexahydrate and ligand is dimethyl glyoxime.

6. The process according to claim 1 and 2, wherein said solvent used in step a) is selected from methanol, ethanol, propanol, butanol, acetone, methylethylketone, methylisobutyl ketone, acetonitrile, ethyl acetate, water or mixtures thereof.

7. The process according to claim 1 and 2, wherein said acid used in step b) for adjusting the pH is selected from acetic acid or hydrochloric acid.

8. The process according to claim 2, wherein said solvent used in step c) is selected from ethylacetate, methylethylketone, methylisobutyl ketone or mixtures thereof.

9. The process according to claim 2 and 3, wherein said base used for neutralization is selected from sodium hydroxide or sodium carbonate.

10. The process according to claim 2 and 3, wherein said solvent used for isolation is selected from ketone solvent such as acetone, butanone, methylethylketone, methylisobutylketone, alcohols such as methanol, ethanol, n-propanol, isopropanol, butanol or mixtures thereof.