Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1996-11-21
2001-10-23
Owens, Amelia (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S214000
Reexamination Certificate
active
06307066
ABSTRACT:
FIELD OF INVENTION
This invention relates to the preparation of SIMVASTATIN. This invention also relates to the purification of intermediates which may be used in the preparation of simvastatin. More broadly, this invention relates to processes for the alkylation at an &agr;-carbon of an ester (containing one or two &agr;-hydrogens) in a molecule which also contains a &bgr;-hydroxylactone functional group with one or two &agr;-hydrogens.
BACKGROUND OF THE INVENTION
Mevastatin (also known as compactin) and lovastatin (also known as mevinolin) are naturally occurring HMG-CoA reductase inhibitors. These compounds have been used medicinally in the control of human serum cholesterol levels. Both compounds contain a (2S)-2-methylbutyryloxy substituent at the C-8 position of their hexahydronaphthalene nucleus and both produce medicinal analogues with increased potency towards HMG-CoA reductase when the aforementioned 2-methylbutyryloxy side chain is converted into a 2,2-dimethylbutyryloxy group. The analogue which is obtained from lovastatin by such a conversion is known as simvastatin. A method for the commercial scale production of simvastatin from lovastatin is the subject of the present invention.
DISCUSSION OF PRIOR ART
Several processes for the preparation of simvastatin from lovastatin are reported. Two of these methods involve a deacylation/reacylation procedure. The prior art discussed in U.S. Pat. No. 4,444,784 (84)/CA1,199,322 (86, Merck) teaches the conversion of lovastatin to several 8-acyloxy derivatives, including simvastatin.
Lovastatin is completely hydrolyzed to remove the 2-methylbutyryl side chain and to simultaneously open its 6-membered lactone ring to produce a trihydroxy acid. The trihydroxy acid compound is then heated in order to effect relactonization and a dihydroxylactone is obtained. The free hydroxy group in the lactone ring of the dihydroxylactone is protected as a tert-butyldimethylsilyl ether and then the hydroxy group at C-8 of the hexahydronaphthalene ring system is esterified using 2,2-dimethylbutyryl chloride. The t-butyldimethylsilyl protecting group is then removed in the final step using tetrabutylammonium fluoride to produce simvastatin.
In U.S. Pat. No. 5,159,104 (92)/CA 2,067,722 (Merck), a deacylation/reacylation approach is also used but an acyl protecting group is used instead of a tert-butyldimethylsilyl group. The dihydroxylactone (obtained as discussed above from lovastatin) is acetylated at the more reactive lactone hydroxy group using acetic anhydride. The acetate which is obtained is then reacted with 2,2-dimethylbutyryl chloride to produce the acetate of simvastatin. The acetate group is then removed by either of two methods. In the first procedure, the acetate of simvastatin is reacted with methanol under acidic conditions to produce a dihydroxy methyl ester. This methyl ester is then reacted with ammonium hydroxide to produce a dihydroxy ammonium salt. The ammonium salt is heated in order to cause relactonization and simvastatin is obtained.
In the second procedure, the acetate of simvastatin is hydrolyzed using an enzymatic preparation.
Previously, it has been reported that lovastatin (in its lactone form) cannot be converted directly to simvastatin by an enolate alkylation reaction because of concurrent alkylation at the lactone &agr;-position (D. Askin, T. R. Verhoeven, H. Liu, and I. Shinkai
J. Org. Chem.
1991, 56, 4929) due to the higher acidity (approximately 3 pKa units) of the lactone &agr;-hydrogens compared with the side chain ester &agr;-hydrogen (K. B. Wiberg, K. E. Laidig
J. Am. Chem. Soc.
1988, 110, 1872). The technologies discussed in U.S. Pat. No. 4,582,915 (86), U.S. Pat. No. 4,820,850 (89)/CA 1,287,063 (91), and U.S. Pat. No. 5,393,893 (95) therefore share a common strategy in which lovastatin is transformed into a protected intermediate wherein the lactone moiety of lovastatin has been intentionally opened. This strategy is undertaken in order to intentionally alter the acidity of the hydrogen atoms which are located at the &agr;-position of the lactone group of lovastatin. The ring opening and protection of the lactone group then allows treatment with a suitable base and hence the removal of the &agr;-proton in the 2-methylbutyryloxy side chain. The enolate species which results is then methylated to produce a 2,2-dimethylbutyryloxy side chain. Protecting groups are then removed, and a thermal reaction is then employed to effect lactonization to produce simvastatin. These three technologies are examined in more detail below.
In the process described in U.S. Pat. No. 4,582,915 (86, Merck), lovastatin is reacted with potassium hydroxide and is converted into a potassium salt of a dihydroxy acid compound. The potassium salt is then enolized using lithium pyrrolidide and the enolate intermediate is alkylated with methyl iodide to produce a dihydroxy acid compound with the 2,2-dimethylated side chain.
The dihydroxy acid is then heated and water is azeotropically removed to produce simvastatin.
In U.S. Pat. No. 5,393,893 (95, Apotex), lovastatin is reacted with cyclohexylamine to open the lactone ring and to produce a lovastatin dihydroxycyclohexylamide. The dihydroxy unit is protected by reacting the intermediate with phenylboronic acid to produce a lovastatin cyclohexylamide boronate. The boronate is alkylated using lithium pyrrolidide and methyl iodide and with an aqueous workup simvastatin cyclohexylamide boronate is produced. The boronate group is removed by hydrolysis with sodium hydroxide to produce a simvastatin cyclohexylamide. The amide group is removed and the lactone ring is reformed by heating with acetic acid.
In U.S. Pat. No. 4,820,850 (89)/CA 1,287,063 (91, Merck), lovastatin is reacted with butylamine to produce lovastatin butylarnide. The two hydroxy groups in the butylamide are protected with tert-butyldimethylsilyl chloride to produce a disilylated lovastatin butylamide. The disilylated lovastatin butylamide is enolized with lithium pyrrolidide and the enolate is alkylated with methyl iodide to produce a disilylated simvastatin butylamide on aqueous workup. The silyl protecting groups are removed using hydrofluoric acid to produce simvastatin butylamide. The simvastatin butylamide is hydrolyzed using sodium hydroxide and, following acidification, the dihydroxy acid form of simvastatin is obtained. The dihydroxy acid compound is reacted with ammonium hydroxide to produce an ammonium salt which is then relactonized by heating to produce simvastatin.
These processes all suffer from severe disadvantages such as excessive steps including those involved with the ring opening of the lactone group of lovastatin, the insertion and removal of protecting groups, and the necessity for relactonization.
It is therefore an object of this invention to provide a process (processes) for the manufacture of simvastatin which is more efficient requiring less steps than in the prior art processes without the problems associated therewith.
It is a further object of this invention to provide a process (processes) for the manufacture of compounds containing a &bgr;-hydroxy lactone group with available lactone &agr;-hydrogens and also an aliphatic ester side-chain with available &agr;-hydrogens wherein alkylation at the ester &agr;-carbon requires less steps than in the prior art processes without the problems associated therewith.
Further and other objects of the invention will be realized by those skilled in the art from the following discussion of the invention, summary of invention and examples thereof.
DISCUSSION OF INVENTION
The present invention relates to the unexpected incorporation of a boronate group in lovastatin and results in deprotonation with high selectivity at the &agr;-position of the 2-methylbutyrate side chain.
SUMMARY OF INVENTION
According to one aspect of the invention, simvastatin may be manufactured by reacting lovastatin with an organic boronic acid to produce a derivative of lovastatin with a boronate group thereafter methylating the 2-methylbutyryloxy group to form the 2,2-dimethylb
Horne Stephen E.
Murthy K. S. Keshava
Weeratunga Gamini
Young Shawn
Brantford Chemicals Inc.
Hughes Ivor M.
Hughes Neil H.
Owens Amelia
Sarkis Marcelo K.
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