Process for producing simvastatin

Details Process for producing simvastatin Process for producing simvastatin

2000-09-28

2001-12-18

Geist, Gary (Department: 1623)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S375000, C560S194000

Reexamination Certificate

active

06331641

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a process for producing a simvastatin which comprises deacylating lovastatin with an inorganic base and a secondary or tertiary alcohol to give a diol lactone and subjecting it serially to selective protection with a ketal or acetal protective group, acylation and deprotection-lactonization. Simvastatin is known to be a compound of use as an HMG-CoA reductase inhibitor.
BACKGROUND ART
The production technology for simvastatin, heretofore known, includes (1) the process comprising hydrolysis of lovastatin with lithium hydroxide, lactonization to give a diol lactone, selective silylation with TBDS, acylation and desilylation (U.S. Pat. No. 4,444,784), (2) the process in which lovastatin potassium salt is directly methylated (U.S. Pat. No. 4,582,915), and (3) the process in which lovastatin monoalkylamide is directly methylated (U.S. Pat. No. 4,820,850), among others.
The above process (1) requires a high temperature and a long time for the hydrolysis reaction so that both yield and productivity are low. Moreover, the selective silylation and subsequent steps are not satisfactory enough in reaction selectivity so that the total yield is not as high as desired. In the process (2), the starting lovastatin partially remains unreacted so that a complicated procedure is required for purification. In the process (3), the reaction must be conducted at an extremely low temperature. Thus, all of the processes have much to be improved for commercial-scale production.
SUMMARY OF THE INVENTION
The inventors of the present invention explored for a technology by which simvastatin may be produced with high efficiency without using costly reagents and under comparatively mild conditions and arrived at a novel process which comprises deacylation of lovastatin with an inorganic base and a secondary or tertiary alcohol and subjecting the resulting diol lactone to selective protection with a ketal or acetal protective group, acylation and deprotection-lactonization to give simvastatin. The present invention has been accordingly developed.
The present invention, therefore, relates to a process for producing a simvastatin of the formula;
which comprises treating lovastatin of the formula (1) with an inorganic base and a secondary or tertiary alcohol to give a triol acid of the formula (2);
serially acidifying and lactonizing the triol acid (2) to give a diol lactone of the formula (3);
treating the triol acid (2) or diol lactone (3) with an acid and a compound of the formula (RO)
2
CR
1
R
2
;
wherein R represents a lower alkyl group of 1 to 8 carbon atoms;
R
1
and R
2
may be the same or different and each represents hydrogen, a lower alkyl group of 1 to 8 carbon atoms, or an aryl or aralkyl group which may have a substituted group, or R
1
and R
2
may be coupled at the free ends to form a ring, to give a triol acid derivative of the formula (4);
 wherein R, R
1
and R
2
are respectively as defined above,
treating the triol acid derivative (4) with 2,2-dimethylbutyryl chloride to give a simvastatin derivative of the formula (5);
 wherein R, R
1
and R
2
are respectively as defined above;
and treating the simvastatin derivative (5) with a protic solvent and an acid to give simvastatin (6).
The present invention further relates to a process for producing a diol lactone (3)
which comprises treating lovastatin (1) with an inorganic base and a secondary or tertiary alcohol to give a triol acid (2),
serially acidifying and lactonizing the triol acid (2) to give a diol lactone (3).
The present invention further relates to a process for producing a triol acid derivative (4)
which comprises treating a triol acid (2) or a diol lactone (3) with an acid and a compound of the formula (RO)
2
CR
1
R
2
; wherein R, R
1
and R
2
are respectively as defined above, to give a triol acid derivative (4).
The present invention further relates to a process for producing a simvastatin derivative (5)
which comprises treating a triol acid derivative (4) with 2,2-dimethylbutyryl chloride to give a simvastatin derivative
The present invention further relates to a process for producing a simvastatin
which comprises treating a simvastatin derivative (5) with a protic solvent and an acid to give simvastatin (6).
Lastly, the present invention relates to a triol acid derivative (4) and a simvastatin derivative (5).


REFERENCES:
patent: 4444784 (1984-04-01), Hoffmann et al.
patent: 5393893 (1995-02-01), Kubela et al.
patent: 6100407 (2000-08-01), Van Dalen et al.
patent: WO 98/12188 (1998-03-01), None
Stretiwieser, A. et al “Introduction to Organic Chemistry” Macmillan Publishing Co., New York, pp. 473-476, 1976.

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