Method for preparing (+) compactin and (+)...

Details Method for preparing (+) compactin and (+)... Method for preparing (+) compactin and (+)...

1997-10-08

2001-08-21

Barts, Samuel (Department: 1621)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06278001

ABSTRACT:

The invention relates to a new process for preparing compounds containing a &bgr;-hydroxy-&dgr;-lactone group which are (+)-compactin and (+)-mevinolin analogues. The process for preparing these products involves new reaction intermediates which are also subjects of the invention, as are the respective processes for preparing them.
HMG-coenzyme A reductase (&bgr;-hydroxy-&bgr;-methylglutaryl-coenzyme A reductase, hereinafter designated HMG-CoA reductase) inhibitors, to which family (+)-compactin and (+)-mevinolin belong, are pharmaceutical active agents used orally in the treatment of hypercholesterolaemia (excessively high plasma cholesterol levels). See, in this connection, the document “Pharmacologie, Des concepts fondamentaux aux applications thérapeutiques” [Pharmacology, From fundamental concepts to therapeutic applications], published under the direction of M. Schorderet, Editions Frison-Roche, second edition, 1992.
These inhibitors are also used in the treatment of diseases associated with the excessive presence of cholesterol, such as arteriosclerosis.
(+)-Compactin (formula 1 below with R═H) and (+)-mevinolin (formula 1 with R═CH
3
) are molecules which are well known for their HMG-CoA reductase inhibiting activity:
In addition, a large amount of work has been developed around the lactone fragment of these molecules. In particular, a review of the syntheses of (+)-compactin and (+)-mevinolin analogues is to be found in the documents Chapleur, Y. “Progress in the chemical synthesis of antibiotics and related microbial products”, Springer Verlag 1993, vol. 2, 829-937 (Doc I) and T. Rosen and C. H. Heathcock, Tetrahedron, Vol. 42, No. 18, 4909-4951, 1986 (Doc II), which analogues have retained the lactone fragment of (+)-compactin and of (+)-mevinolin and possess a lipophilic portion which is simplified relative to the latter compounds. However, none of the synthesis routes known for such molecules is satisfactory.
The main synthesis routes for the lactone fragment of the lactone 1, in optically active form, use chiral commercial starting materials such as maleic acid or 2-glutamic acid (M. Majewski et al., Tet. Lett. 1984, 25, 2101; T. Minami et al., Tet. Lett. 1993, 34, 513) or carbohydrates (M. Menges et al., Synlett 1993, 901;M. S. Ernolenko et al., Tet. Lett. 1994, 35, 715). Others comprise an asymmetric reduction step with rhodium-based catalysts (M. Terada et al., Tet. Lett. 1991, 32, 935; L. Shao et al., Tet. Lett. 1991, 32, 7699) or enzymatic reducing agents (F. Bennet et al., J. Chem. Soc. Perkin Transfer I, 1991, 133; M. H. Ansari, Tet. Lett. 1993, 34, 8271).
These syntheses are not without their drawbacks. In particular, the chiral starting materials employed in some of these syntheses are expensive, and catalysts enabling an asymmetric reduction to be induced are likewise very expensive. Moreover, enzymatic asymmetric reductions give enantiomeric excesses which do not exceed 80%.
Syntheses which do not have these drawbacks are also known, such as the one described in Tet. Lett., Vol. 35, No. 5, 715-718, 1994, but necessitate the use of dangerous reactants and solvents such as pyridine and tributyltin.
Thus, the applicant was surprised to discover a new synthesis route for (+)-compactin and (+)-mevinolin analogues. This synthesis route, which is easy to carry out and can be extrapolated to the industrial scale, uses an inexpensive starting material, a chiral agent which can be manufactured industrially and is of moderate cost. Furthermore, the method affords good yields, and the products of this synthesis are obtained with an excellent enantiomeric purity (>98%). In addition, this synthesis route enables access to be gained to new (+)-compactin and (+)-mevinolin analogues.
The subject of the invention is a new process for preparing the products corresponding to one of the formulae (Ia) and (Ib):
in which &PSgr; represents a radical chosen from:
saturated or unsaturated, linear, branched or cyclic C
1
-C
40
alkyls, optionally interrupted by ether bridges and/or optionally substituted with one or more substituents chosen from halogen, hydroxyl, C
1
-C
20
alkoxy, C
1
-C
20
acyloxy, primary, secondary or tertiary amino, nitro, thiol, carboxyl, amido, C
1
-C
20
alkyl carboxylate, aryl carboxylate, C
1
-C
20
aralkyl carboxylate, C
1
-C
20
alkylamido, arylamido and C
1
-C
20
aralkylamido groups, and from aryl radicals and saturated or unsaturated C
1
-C
20
nitrogen, oxygen, phosphorus and sulphur heterocycles;
aryls, optionally substituted with one or more substituents chosen from halogen, hydroxyl, C
1
-C
20
alkoxy, C
1
-C
20
acyloxy, amino, C
1
-C
20
alkylamino and dialkylamino, nitro, thiol, carboxyl, amido, C
1
-C
20
alkyl carboxylate, aryl carboxylate, C
1
-C
20
aralkyl carboxylate, C
1
-C
20
alkylamido, arylamido, C
1
-C
20
aralkylamido and C
1
-C
20
aryl groups, and from saturated or unsaturated, linear, branched or cyclic C
1
-C
20
alkyl and aralkyl radicals and saturated or unsaturated C
1
-C
20
nitrogen, oxygen, phosphorus and sulphur heterocycles;
aralkyls, optionally substituted with one or more substituents chosen from halogen, hydroxyl, C
1
-C
20
alkoxy, C
1
-C
20
acyloxy, amino, C
1
-C
20
alkylamino and dialkylamino, nitro, thiol, carboxylic acid, amido, C
1
-C
20
alkyl carboxylate, aryl carboxylate, C
1
-C
20
aralkyl carboxylate, C
1
-C
20
alkylamido, arylamido, C
1
-C
20
aralkylamido and C
1
-C
20
aryl groups, and from saturated or unsaturated, linear, branched or cyclic C
1
-C
20
alkyl and aralkyl radicals;
nitrogen, oxygen, phosphorus or sulphur heterocycles, optionally substituted with one or more substituents chosen from halogen, hydroxyl, C
1
-C
20
alkoxy, C
1
-C
20
acyloxy, primary, secondary or tertiary amino, nitro, thiol, carboxylic acid, amido, C
1
-C
20
alkyl carboxylate, aryl carboxylate, C
1
-C
20
aralkyl carboxylate, C
1
-C
20
alkylamido, arylamido and C
1
-C
20
aralkylamido groups, and from aryl and aralkyl radicals and saturated or unsaturated C
1
-C
20
nitrogen, oxygen and sulphur heterocycles.
The formulae (Ia) and (Ib) cover a very large number of products, the extent of which in the field of HMG-coenzyme A reductase inhibitors is illustrated by the documents “Progress in the chemical synthesis of Antibiotics and related microbial products”, Y. Chapleur, Vol. 2, 1993, 829-937, G. Lukacs Ed. Springer Verlag (Doc I); T. Rosen and C. H. Heathcock, Tetrahedron, Vol. 42, No. 18, 4909-4951, 1986 (Doc II) and J. Prous “The year's drug news, therapeutic targets, 1994 edition”, Prous science Publishers (Doc III). Besides the products mentioned in these documents, the process which is the subject of the present invention permits ready access to many other molecules corresponding to the formulae Ia and lb.
Among the radicals represented by &PSgr;, there may be mentioned, for example, the radicals corresponding to the following formulae and which correspond to the products of formula (Ia) which are known to be HMG-coenzyme A reductase inhibitors:
Described in Doc I:
Described in Doc III:
The products of formula (Ia) and of formula (Ib) contain at least two asymmetric carbons. Thus, the subject of the invention is a process for preparing each of the four diastereoisomers corresponding to one of the formulae (Ia) or (Ib), taken separately, as well as the mixtures thereof, racemic or otherwise.
The subject of the invention is a process for preparing the products of formula (Ia) and (Ib) characterized in that:
1) in a first step, the tri-anion of the alkyl 3,5-dioxohexanoate of formula (X) shown below is reacted with (−)- or (+)-menthyl (X's)-p-toluenesulphinate (p-toluene designated pTol) to obtain the alkyl (Xs)-3,5-dioxo-6-(p-tolylsulphinyl)hexanoate of formula (II),
Y—CO—CH
2
—CO—CH
2
—CO—CH
3
  (X)
Xs and X's denoting the R or S configurations of the sulphur in the two molecules, with Xs≠X's, Y representing a saturated or unsaturated, linear or branched C
1
-C
18
al

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