Highly purified simvastatin compositions

Details Highly purified simvastatin compositions Highly purified simvastatin compositions

2001-07-26

2004-02-03

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S420000

Reexamination Certificate

active

06686481

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process to prepare semi synthetic statins, to intermediates formed during said process and to highly purified simvastatin produced by the process.
BACKGROUND OF THE INVENTION
Statin drugs are currently the most therapeutically effective drugs available for reducing the level of LDL in the blood stream of a patient at risk for cardiovascular disease. This class of drugs includes lovastatin, simvastatin, pravastatin, compactin, fluvastatin and atorvastatin.
Simvastatin is the common medicinal name of the chemical compound butanoicacid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S*-[1a,3a,7b,8b(2S*,4S),-8ab]]. (CAS Registry No. 79902-63-9.) The molecular structure of simvastatin is shown below with atoms labeled to indicate numbering of the atoms.
Lovastatin is the common medical name of the chemical compound [1S-[1&agr;(R*),3&agr;,7&bgr;;8&bgr;(2S*,4S*),8a&bgr;]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl ethyl]-1-naphthalenyl 2-methylbutanoate. (CAS Registry No. 75330-75-5.) The molecular structure of lovastatin is shown below with atoms labeled to indicate numbering of the atoms.
Lovastatin possess a 2-methylbutyryl ester side chain at the 8-position of the hexahydronaphthalene ring system. In contrast, simvastatin possess a 2,2-dimethylbutyryl side chain at the 8-position of the hexahydronaphthalene ring system. It is known that simvastatin is a more effective agent than lovastatin for reducing the level of LDL in the blood stream.
The prior art discloses methods for converting lovastatin to simvastatin. U.S. Pat. No. 4,582,915, incorporated herein by reference, discloses converting mevinolin, compactin and dihydro- and tetrahydro derivatives thereof to more active HMG-CoA reductase inhibitors by C-methylation of the natural 2(S)-methylbutyryloxy side chain to form a 2,2-dimethylbutyryloxy side chain.
U.S. Pat. No. 5,223,415 incorporated herein by reference, discloses the enzymatic hydrolysis of lovastatin acid, by treating lovastatin acid with Clonostachys compactiuscula ATCC 38009 or ATCC 74178, or a cell-free extract derived therefrom. The product is an inhibitor of HMG-CoA reductase and thus useful as anti-hypercholesterolemic agents. The product also serve as an intermediate for preparation of other HMG-CoA reductase inhibitors.
U.S. Pat. No. 4,293,496 incorporated herein by reference, discloses removal of the 2-methylbutyryl side chain by base hydrolysis of the ester of lovastatin with an alkali metal hydroxide, preferably LiOH. The products are useful as intermediates in the synthesis of antihypercholesterolemia agents.
U.S. Pat. No. 4,444,784, incorporated herein by reference, discloses the introduction of a new side chain to hydrolyzed lovastatin.
U.S. Pat. No. 5,159,104, incorporated herein by reference, discloses the formation of simvastatin, by the sequential acylation of a diol lactone to form a bis acylated intermediate followed by selective deacylation and lactone ring closure to form simvastatin.
SUMMARY OF THE INVENTION
The present invention provides substantially pure simvastatin which comprises less than about 0.1 weight % simva-oxolactone.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % anhydrosimvastatin.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % simvastatin dimer.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % dihydrosimvastatin.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % at least one compound selected from the group consisting of simva-oxolactone, anhydrosimvastatin, simvastatin dimer and dihydrosimvastatin.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % simva-oxolactone.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % anhydrosimvastatin.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % simvastatin dimer.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % dihydrosimvastatin.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % of at least one compound selected from the group consisting of simva-oxolactone, anhydrosimvastatin, simvastatin dimer and dihydrosimvastatin.
According to another aspect, the present invention relates to a process for the formation of highly purified simvastatin from lovastatin, comprising the steps of: lactone ring opening by reacting lovastatin with an amine to form an amid; protecting a 1,3-diol moiety with a protecting group; removing a 2-methylbutyryl group attached by an ester linkage through an oxygen at position 8 of a hexahydronaphthalene ring; attaching a 2,2-dimethylbutyrate group by forming an ester linkage to a hydroxyl at position 8; removal of a protecting group; conversion of the amid to an acid salt; and, lactone ring closing to form simvastatin.
According to another aspect, the present invention relates a process for the formation of a semisynthetic statin of Formula I,
from a statin of Formula II,
which comprises the steps of: lactone ring opening by reacting the statin of Formula II with an amine to form an amid; protecting a 1,3-diol moiety with a protecting group; removing a 2-methylbutyryl group attached by an ester linkage through an oxygen at position 8 of a hexahydronaphthalene ring; attaching a 2,2-dimethylbutyrate group by forming an ester linkage to a hydroxyl at position 8; removal of the protecting group; conversion of the amid to an acid salt; and, lactone ring closing to form the semisynthetic statin of Formula I wherein R
1
and R
2
are both acyl groups linked to the oxygen through an ester bond and R
3
and R
4
are independently selected from the group consisting of —H, —OH, —C
1-10
alkyl, —C
6-14
aryl, and —C
6-14
aryl-C
1-3
.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides substantially pure simvastatin which comprises less than about 0.1 weight % simva-oxolactone.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % anhydrosimvastatin.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % simvastatin dimer.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % dihydrosimvastatin.
The present invention also provides substantially pure simvastatin which comprises less than about 0.1 weight % at least one compound selected from the group consisting of simva-oxolactone, anhydrosimvastatin, simvastatin dimer and dihydrosimvastatin.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % simva-oxolactone.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % anhydrosimvastatin.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % simvastatin dimer.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % dihydrosimvastatin.
The present invention also provides a pharmaceutical composition comprising substantially pure simvastatin and less than about 0.1 weight % of at least one compound selected from the group consisti

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