A PROCESS FOR PURIFICATION OF LOVASTATIN

Field of the Invention
The present invention relates to a process for the purification of lovastatin that reduces the level of unknown impurities to below 0.10%. Also  such a process is short  less time taking  and industrially viable. The invention also relates to the use of purified lovastatin for the synthesis of simvastatin to furnish subsequently pure simvastatin.

Background of the Invention
Lovastatin is a member of the drug class of statins  used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is an inhibitor of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA reductase)  an enzyme that catalyzes the conversion of HMG-CoA to mevalonate.

As the first commercial product of the HMG-CoA reductase inhibitors (statins)  Lovastatin is widely used for cholesterol lowering. Meanwhile it is also the key material in the manufacture of simvastatin. In industry  purification of Lovastatin was achieved by several methods one of the purification methods is several times of recrystallization.

Lovastatin of formula (I) known chemically as (1S  3R  7S  8S  8a R)1 2 3 7 8 8a-hexahydro-3 7-dimethyl-8-[2-[(2R 4R)tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-napthalenyl-(S) -2-methylbutyrate is disclosed in U.S. Pat. No. 4 231 938

Formula (I)
Hypercholesterolemia is known to be a major risk factor for atherosclerosis. Complications of cardiovascular disease  such as myocardial infarction  stroke  and peripheral vascular disease result in many deaths in developed countries. A decrease in plasma LDL levels has been shown to reduce the risk of cardiovascular disease. Statins are by far the most therapeutically effective drugs for reducing the plasma LDL levels. Statins include for example  lovastatin  compactin  pravastatin  simvastatin which are essentially fermentation based and rosuvastatin  fluvastatin and atorvastatin which are totally synthetic statins.

Several processes are reported for recovering lovastatin from fermentation broth which suggest use of different solvents for extraction  recrystallization  use of different chromatographic methods for purification of lovastatin  and the like for example  in U.S. Patent No. 4 916 239; 4 231 938; 5202029; International Publication Nos. (PCT) WO 00/63411 and WO 03/48149.

Several methods are known for isolation of Lovastatin (I) through lactonisation of Mevinolinic acid and purification of impure lovastatin to give pure form of lovastatin  which are summarized herein below:

US Patent No. 4 231 938 (Monaghan R. L et al.) describes a method for purification by column chromatography on silica gel. This method has very little industrial application since it involves purification by chromatography.

PCT Publication No. WO 1997/20834 A1 (Dimov I et al.) describes a method for purification of Lovastatin by treating the culture broth with alkaline base in presence of an antioxidant  the filtered and dried raw lovastatin dissolved in a nitrile such as acetonitrile or propionitrile  the solution obtained was decolorized by treating with a mixture of activated carbon and aluminium oxide after addition of water  lovastatin is precipitated at room temperature. This is recrystallized twice successively in a mixture of solvent followed by recrystallization in acetone at -10 to -30ºC.

PCT Publication No. WO 2006035295 A1 (Kumar et al.) describes a method for purification of Lovastatin by obtaining a solution of lovastatin in toluene  recovering lovastatin  recrystallizing the lovastatin from one or more solvents and recovering the substantially pure lovastatin by the removal of the solvents.

US Patent No. 6 388 100 (Vilmos Keri et al.) describes the process for reducing the dimeric impurities in a statins to less than 0.08% by treatment of statins containing more than 0.08% dimeric impurity with a mild base in a suitable solvent mixture. The mild base includes aliphatic mono  di or tri-amine  aromatic amine  ammonium hydroxide and ammonia. Process requires cooling to -20ºC for 24 hours.

Indian Patent No. IN 181828 and IN 181829 describes a method for purification of Lovastatin by recrystallization from methanol or ethanol.

US Patent No. 5 202 029 (Haytko P. N et al.) claims a method for purification of Lovastatin using high performance liquid chromatography (HPLC) using C-18 silica packed HPLC column and eluting with mixture of acetonitrile and water  concentrating the pure fraction to a certain extent and crystallizing by addition of water. This method of purification is not suited for industrial use due to its high cost.

Looking in to cumbersome processes used in the prior art  there is need to develop a simpler  shorter  industrially viable and cost effective purification process which does not involve any chromatographic technique or repeated crystallization.

The present invention provides a purification process that has overcome the drawbacks of the above prior arts.

Summary of the Invention
It is an object of the present invention to provide a process for purification of lovastatin.

One aspect of the present invention is to provide a process for purification of lovastatin to reduce any unknown impurities to below 0.10%.

The present invention also provides a process for purification of lovastatin that reduces any unknown impurities to below 0.1  and said process is short  less time taking  and industrially viable.

The present invention also provides a process for purification of lovastatin  wherein the process comprises: dissolving lovastatin in a mixture of hydrocarbon and alcohol  treating the solution with activated charcoal  filtering to obtain a filterate  and isolating the pure lovastatin from said filterate by crystallization  and wherein such process reduces any unknown impurities to below 0.10%.

The present invention also provides a process for purification of lovastatin which is short  less time taking  industrially viable and capable of reducing any unknown impurities to below 0.10%  wherein the process comprises:
(i) dissolving lovastatin in a mixture of hydrocarbon and alcohol 
(ii) treating the solution with activated charcoal
(iii) filtering to obtain a filtrate  and
(iv) isolating the pure lovastatin from said filtrate by crystallization.

The present invention also provides a purified lovastatin  wherein any unknown impurities in the compound is below 0.10%.

Another aspect of the invention relates to a method for purification of lovastatin and use of purified lovastatin for the synthesis of simvastatin to furnish subsequently pure simvastatin with good yield.

Description of the Accompanying Drawings
Fig-1: HPLC chromatogram of pure lovastatin showing unknown impurities below 0.10%
Fig-2: HPLC chromatogram of pure simvastatin prepared from purified lovastatin

Detailed Description of the Invention
Fermentation process for the synthesis and lactonization process for the production of lovastatin result in the formation of lots of unwanted impurities. These impurities are hard to remove as they crystallize along with the product. There are many methods in prior art to remove these impurities like silica gel column chromatography  high performance liquid chromatography and crystallization process. Crystallization process is most suitable purification process for industrial production of lovastatin but these methods are lengthy  time taking and involve many steps.

The present invention provides a process of purification of lovastatin  which reduces the level of any unknown individual impurities to below 0.10%. The present invention provides a process of purification of lovastatin  which reduces the purification steps to single step. And the present invention provides a process of purification of Lovastatin  which reduces the time of purification process as well.

In present invention the solvent mixture is used to remove the polar as well as non polar impurities in a single crystallization to reduce the purification process time.

The mixture of solvent comprises a hydrocarbon and other component  the hydrocarbon component of the mixture can be toluene  benzene  chlobenzene and other aromatic hydrocarbon. The other component of the solvent mixture can be an alcohol like methanol  ethanol and Isopropanol.

The present invention provides a process of purification of lovastatin which is short  less time taking  industrially viable and capable of reducing any unknown impurities to below 0.10%.

The present invention provides a process for purification of lovastatin to reduce any unknown impurities to below 0.10%  wherein the process comprises:
dissolving lovastatin in a mixture of hydrocarbon and alcohol 
treating the solution with activated charcoal 
filtering to obtain a filtrate  and
isolating the pure lovastatin from said filtrate by crystallization.

The said process for purification of lovastatin is short  less time taking  and is industrially viable.

The hydrocarbon employed in the present invention is an aromatic hydrocarbon. The aromatic hydrocarbon is selected from toluene  benzene and chlorobenzene.

The alcohol employed in the present invention is a C1-C4 alcohol. The alcohol is selected from methanol  ethanol and isopropanol.

The mixture of alcohol and hydrocarbon employed in the present invention is in the ratio of 1:9 to 9:1 and preferably 1:9.

The dissolution and activated charcoal treatment steps in the process are carried out at a temperature range of room temperature to 100ºC  preferably 50ºC to 80ºC  and more preferably 65ºC to 70ºC.

The filtration step in the process is carried out at a temperature range of room temperature to 100ºC  preferably 50ºC to 80ºC  and more preferably 65ºC to 70ºC.

The crystallization step in the process is carried out at a temperature range of 0ºC to 40ºC  preferably 0ºC to room temperature  and more preferably 0ºC to 5ºC.

The crystallization step in the process is carried out for a period of 15 minutes to 12 hours  preferably for 3 to 4 hours.

The present invention also provides a process for purification of lovastatin and use of purified lovastatin for the synthesis of simvastatin to furnish subsequently pure simvastatin with good yield.

Comparison of the impurity profile of present invention with that of other purification process is summarized in the table given below

Parameters Crystallization solvents or solvent mixture
Present Invention(Solvents used )* Toluene MeOH Toluene followed by MeOH MIBK EtOH IPA Butanol Acetone
Chromatographic purity (%) 99.62 99.18 99.26 99.39 99.23 99.26 99.30 99.46 99.10
Impurity-D (Dimmer) (%) 0.11 0.14 0.20 0.19 0.16 0.29 0.21 0.22 0.16
Single maximum impurity (%) 0.09 0.24 0.14 0.14 0.15 0.16 0.18 0.09 0.20
*Solvents used Methanol and Toluene
MeOH: Methanol
EtOH: Ethanol
MIBK: Methyl ethyl ketone
IPA: Isopropyl alcohol
Advantages of the present invention
1. The present invention provides a very short and less time taking process for the purification of lovastatin  which is capable of reducing the unknown impurities to below 0.10%.
2. The present invention provides an industrially viable process for the purification of lovastatin. As lovastatin is more soluble in the mixture of solvent than the individual solvent  the bigger batch size can be taken.
3. The present invention provides a very short and less time taking process for the purification of lovastatin which involves fewer industrial equipments.
4. The present invention does not involve purification by chromatographic techniques.
5. The present invention provides a process for the purification of lovastatin  which can be used for the synthesis of subsequently pure simvastatin.

The purification of lovastatin by the new processes of this invention is now illustrated with reference to the following Examples  to which this invention is not limited.

Example-1

Purification of lovastatin

50g of impure lovastatin (assay 96.33%) was added to a mixture of methanol (20ml) and toluene (180ml) under stirring at room temperature  resulting suspension was heated to 65-70° C to dissolve the solid  activated charcoal (2.5g) was added to the clear solution  stirred further for 60 minutes at 65-70° C followed by hot filtration  filtrate cooled to 0-5° C and stirred at 0-5° C for four hours  solid filtered washed with toluene and dried to furnish (36g) pure lovastatin having a chromatographic purity 99.57%  assay 99.85%  dimmer impurity 0.11% and other individual impurity 0.09%

S.N. Input Output
Qty. (g) Purity (%) SMI (%) Imp-D (%) Assay (%) Qty. (g) Purity (%) SMI (%) Imp-D (%) Assay (%)
2 50.0 98.74 0.18 0.26 96.23 36.0 99.57 0.09 0.11 99.85
SMI = Single maximum impurity

Example-2

Purification of lovastatin

250g of impure lovastatin (assay 96.33%) was added to a mixture of methanol (100ml) and toluene (900ml) under stirring at room temperature  resulting suspension was heated to 65-70° C to dissolve the solid  activated charcoal (12.5g) was added to the clear solution  stirred further for 60 minutes at 65-70° C followed by hot filtration  filtrate cooled to 0-5° C and stirred at 0-5° C for four hours  solid filtered washed with toluene and dried to furnish (36g) pure lovastatin having a chromatographic purity 99.62%  assay 99.36%  dimmer impurity 0.11% and other individual impurity 0.09%.

S.N. Input Output
Qty. (g) Purity (%) SMI (%) Imp-D (%) Assay (%) Qty. (g) Purity (%) SMI (%) Imp-D (%) Assay (%)
1 250.0 98.80 0.18 0.28 96.23 170.0 99.62 0.09 0.11 99.36
SMI = Single maximum impurity

While this invention has been described in detail with reference to certain preferred embodiments  it should be appreciated that the present invention is not limited to those precise embodiments. Rather  in view of the present disclosure  which describes the current best mode for practicing the invention  many modifications and variations would present themselves to those skilled in the art  without departing from the scope of this invention.

We Claim:

1. A process for purification of lovastatin comprising:
dissolving lovastatin in a mixture of hydrocarbon and alcohol 
treating the solution with activated charcoal 
filtering to obtain a filtrate  and
isolating the pure lovastatin from said filtrate by crystallization 
wherein said process reduces any unknown impurities to below 0.10%.
2. The process according to claim 1  wherein the hydrocarbon is an aromatic hydrocarbon.
3. The process according to claim 2  wherein the aromatic hydrocarbon is selected from toluene  benzene and chlorobenzene.
4. The process according to claim 1  wherein the alcohol is a C1-C4 alcohol.
5. The process according to claim 4  wherein the alcohol is selected from methanol  ethanol and isopropanol.
6. The process according claim 1  wherein the mixture of alcohol and hydrocarbon is in the ratio of 1:9 to 9:9  preferably 1:9.
7. The process according to claim 1  wherein the temperature for the dissolution and activated charcoal treatment is room temperature to 100ºC  preferably 50ºC to 80ºC  and more preferably 65ºC to 70ºC.
8. The process according to claim 1  wherein the temperature for filtration is room temperature to 100ºC  preferably 50ºC to 80ºC  and more preferably 65ºC to 70ºC.
9. The process according to claim 1  wherein the temperature for the crystallization is 0ºC to 40ºC  preferably 0ºC to room temperature  and more preferably 0ºC to 5ºC.
10. The process according to claim 1  wherein the time for the crystallization is 15 minutes to 12 hours  preferably 3 to 4 hours.
11. A purified lovastatin  wherein any unknown impurities in the compound is below 0.10%.