Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-08-11
1994-04-19
Chan, Nicky
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D30910
Patent
active
053046609
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
This invention relates to new intermediates, to a process for their preparation, to their use in the preparation of pharmaceuticals, and to pharmaceuticals prepared therefrom.
The new intermediates of the present invention are the compounds of general formula I hereinafter depicted wherein R.sup.1 represents a straight- or branched-chain alkyl group containing from 1 to about 4 carbon atoms, preferably methyl or isopropyl, R.sup.2 represents an acid-labile protecting group, preferably a triphenylmethyl group, and X.sup.1 represents a halogen, preferably bromine or iodine, atom.
The compounds of formula I are key intermediates in a new reaction sequence which permits the stereospecific preparation of analogues of mevalonic acid without the necessity to use potentially hazardous mercury compounds employed in previously known processes described, for example, by Rosen et al, J. Org. Chem., 1984, 49, 3994-4003 and Corey et al, J. Am. Chem. Soc., 1980, 102, 1439.
The said analogues of mevalonic acid are valuable pharmaceutically active compounds, more especially competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and are consequently inhibitors of cholesterol biosynthesis and as a result are of use in the prevention or treatment of hypercholcsterolaemic and hyperlipoproteinaemic states, atherosclerosis and associated conditions.
Examples of such mevalonic acid analogues are described, for example, in the specifications of our granted South African Patents Nos. 88/5852 and 89/0645 and of their equivalents in other countries, for example United States Patent Applications Nos. 07/230,038, now U.S. Pat. No. 4,933,350, and 07/302,389, now abandoned in favor of a file wrapper continuation Ser. No. 494,956, now U.S. Pat. No. 5,004,747.
According to a feature of the present invention, compounds of formula I are prepared by the reaction of compounds of general formula II hereinafter depicted, wherein R.sup.2 is as hereinbefore defined, with a halogenating agent, e.g. N-iodosuccinimide when X.sup.1 represents iodine and N-bromosuccinimide when X.sup.1 represents bromine, and the appropriate alcohol of the general formula: act as the solvent medium alone or with one or more additional solvents such as polar aprotic solvents, e.g. acetonitrile.
According to a further feature of the present invention, the compounds of formula I are then hydrogenated, using a hydrogenation catalyst such as palladium on charcoal or Raney nickel, in the presence of a base, for example triethylamine or an alkali metal hydroxide, e.g. potassium hydroxide, to form compounds of general formula IV hereinafter depicted, wherein R.sup.1 and R.sup.2 are as hereinbefore defined
The hydrogenation is preferably carried out in an organic solvent, for example a lower alkanol containing up to about 3 carbon atoms, e.g. methanol or ethanol, especially when an alkali metal hydroxide is used as the base, a lower ester, e.g. methyl or ethyl acetate, or an aromatic solvent, e.g. toluene, at about 10.degree.-60.degree. C., preferably 20.degree.-50.degree. C. and preferably at about 40-60 p.s.i.
According to a further feature of the present invention, compounds of formula IV are elaborated to prepare the said mevalonic acid analogues, by the application or adaptation of known methods
Compounds of formula II may be prepared by the application or adaptation of known methods, for example as described by Fraser-Reid et al, Can. J. Chem., 51, 3950 (1973). ##STR2##
The following Examples illustrate the present invention.
Nuclear Magnetic Resonance (NMR) spectra are conducted in solution in CDCl.sub.3 and the chemical shifts are given in ppm with tetramethylsilane as reference. The following abbreviations are used: "s" means "singlet", "d" means "doublet", "q" means "quadruplet" and "m" means "multiplet".
EXAMPLE 1
A stirred solution of 3.alpha.,4.beta.-dihydroxy-2.beta.-triphenylmethoxymethyl-3,4-dihydropyran (5 g) in methanol (50 ml) at 0.degree. C. was treated with N-iodosuccinimide (4.4 g) during 15 minutes, maintaining the temp
REFERENCES:
patent: 4677211 (1987-06-01), Jewell, Jr. et al.
Canadian Journal of Chemistry, vol. 42, pp. 532-538, 1964, The Bromination and Halogenomethoxylation of D.varies.Glucal Triacetate.
J. Org. Chem., vol. 49, No. 21, pp. 3994.varies.4003, 1984, Synthetic and Biological Studies of Compactin and Related Compounds. 2. Synthesis of the Lactone.
Clark Stanley F.
Jones Ronald H.
Newton Christopher G.
Chan Nicky
Parker III Raymond S.
Rhone-Poulenc Rorer S.A.
Savitzky Martin F.
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