Process for the preparation of simvastatin and derivatives...

Details Process for the preparation of simvastatin and derivatives... Process for the preparation of simvastatin and derivatives...

2000-09-22

2001-06-26

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S214000

Reexamination Certificate

active

06252091

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to a process for the preparation of the HMG-CoA-reductase inhibitor simvastatin and derivatives thereof.
Simvastatin is a semi-synthetic analog of the natural fermentation product lovastatin which has a 2-methylbutyrate side chain in the 8-position of the hexahydronaphthalene ring system. It has been discovered that the replacing of the 2-methylbutyrate group by a 2,2-dimethylbutyrate group results in more active inhibitors of HMG-CoA reductase (J. Med. Chem., 1986, 29(5), 849-852).
TECHNICAL PROBLEM
Heretofore, the preparation of simvastatin and derivatives thereof was only possible in low yield. The prior art processes also suffer from the drawback that large amounts of unconsumed starting materials remain after completion of the reaction. These starting materials as well as substantial amounts of undesired by-products formed during the process result in complications when recovering the product. Thus, there exists a need for a process overcoming theses problems.
BACKGROUND OF THE INVENTION
The known processes for preparing simvastatin and derivatives thereof can basically be divided according to two synthesis approaches used, namely (a) the so-called re-esterification route and (b) the direct methylation of the methyl butyrate side chain.
An example for the first synthetic approach is described in EP-B-33 538. It discloses a five-step process which comprises the steps of (1) exhaustive saponification of lovastatin; (2) relactonisation; (3) selective silylation; (4) re-acylation; and (5) desilylation. The reported overall yields obtained by this process are low, namely just 48% (J. Org. Chem 56, 4929 (1991)). This is partly attributable to the low yield of 69% obtained in the selective silylation step (3). Further, the re-acylation (4) is carried out at a high temperature of 100° C. for prolonged time (18-36 hours) in the presence of 4-pyrrolidino pyridine or dialkylamino pyridine. These reaction conditions lead to formation of a substantial amount of undesired by-product (unsaturated lactone) resulting from the elimination of the tert.-butyldimethylsilyloxy radical, present as protecting group of the alcohol, from the &dgr;-valerolactone moiety. Finally, also large amounts of starting diol lactone and unconsumed acid chloride remain at the end of the reaction.
In EP-B-287340 an improved acylation process for the preparation of antihypercholesterolemic compounds is disclosed which comprises the combining of a suitable acid chloride with an alkali metal bromide, dialkylaminopyridine and a polyhydronaphthyl alcohol to obtain the corresponding acylated product. The reaction is carried out at a relatively high temperature of 70° C. so the unsaturated lactone by-product is also formed in an amount of about 1-2%. Moreover, the preferred solvent used in this process is pyridine which is environment and people unfriendly.
The second synthesis approach, the direct alkylation of the methyl butyrate side chain, is disclosed in EP-B-137 445 and EP-B-299 656. The processes involve use of a metal alkyl amide and methyl halide. The main disadvantage of these processes is the contamination of the product by a significant amount of unconverted starting materials, e.g. lovastatin. Since simvastatin and lovastatin differ only by one methyl group, it is very difficult to isolate simvastatin from a mixture containing both by means of conventional separation methods. Thus, an additional purification step is normally required, for example the selective hydrolysis of residual lovastatin as per the method disclosed in WO 93/16188.
N-methylimidazole, also referred to as 1-methylimidazole, is a known compound useful for the acetylation of hydroxy compounds with acetic anhydride (see Anal. Chem. 50, 1542-1545 (1978)). However, the reaction with sterically hindered alcohols gives only a poor yield. In case of tert.-butyl alcohol the yield is only 36%.
Moreover, in Anal. Chem. 52, 572 (1980) it is described that N-methylimidazole can also be employed as a catalyst for the acetylation of hydoxyl-terminated polymers by acetic anhydride.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention a process for the preparation of compounds of formula (I)
wherein
R is a C
1
to C
12
alkyl group and
R
1
is a protecting group or H
is provided which process comprises
(a) converting the diol lactone of formula (II)
 to the protected diol lactone of formula (IIa) wherein R
1
is a protecting group
(b) acylating the protected diol lactone (IIa) to give compound (I) wherein R
1
is a protecting group, and
(c) optionally removing protecting group R
1
to give compound (I) where R
1
is H, and
wherein steps (a) and/or (b) are carried out in the presence of N-methylimidazole.
The compounds of formula (I) are effective antihyper-cholesterolemic compounds and include in particular simvastatin. In formula (I) the group R can be a C
1
to C
12
branched or straight alkyl group or a C
3
to C
1
cyclic alkyl group, preferably a C
5
alkyl group and in particular CH
3
—CH
1
—C(CH
3
)
2
—.
Suitable examples of protecting groups R
1
are groups conventionally used for selectively protecting hydroxy groups, such as silyl groups. Preferred are trialkyl silyl groups, such as isopropyldimethylsilyl, (triphenylmethyl)dimethylsilyl, tert.-butyldiphenylsilyl, methyldiisopropylsilyl, tribenzylsilyl, triisopropylsilyl and a particularly preferred example is the tert.-butyldimethysilyl group.
It was surprisingly shown that the compounds (I) can be prepared by the acylation process according to the invention in a very efficient manner and with high yield without formation of substantial amounts of undesired by-product. It was found that particularly good results are obtained if N-methylimidazole is present in both process step (a) and (b). Thus, N-methylimidazole seems to act as a catalyst not only for the protection step (a) but also for the acylation step (b) resulting in an excellent overall yield.
The diol lactone (II) used in step (a) is for example available by hydrolysation of lovastatin according to the method disclosed in EP-B-33 538.
In case of the introduction of a silyl group, such as the tert.-butyldimethyl silyl group, as a protecting group, the yield obtained in step (a) is virtually 100%. As practically no by-products are formed in step (a), it is possible to carry step (a) and (b) as a one-pot reaction without the need to isolate the formed protected diol lactone (IIa). This preferred embodiment of the invention greatly simplifies the preparation of the desired compound (I) . It was also found out that due to the presence of N-methylimidazole the reaction time for completing (a) is decreased and is normally only 1.5 to 4 h.
The N-methylimidazole is preferably used in an amount sufficient to dissolve at the chosen reaction temperature the diol lactone (II) and the protected diol lactone (IIa), respectively. It therefore can also serve as a solvent. Due to the possibility of employing it in step (a) and (b) there is no necessity to change the solvent after completion of step (a) which is very advantageous when carrying out a one-pot synthesis.
In contrast to prior art processes steps (a) and/or (b) can be carried out at low temperatures and in particular in the range of about 0 to about 30° C. The low reaction temperature especially when conducting the acylation reaction (b) results in a substantial reduction of the level of by-products, such as unsaturated lactone by-product. In the prior art methods the acylation step requires temperatures of 100° C. or 70° C.
The acylating step (b) is preferably carried out by reacting the protected diol lactone (IIa) with a suitable activated form of the acid of formula (III)
R—CO—OH  (III)
Preferred activated forms are the corresponding acid anhydrides or acid halogenides. Particularly suitable are acid chlorides. The acid halogenides or acid anhydrides are commercially available compounds or can be prepared from known starting materials utilising standard chemical transformations.
It was surprisingly fou

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