DERIVATIVES OF PYRAN

Abstract: The invention provides a process for the preparation of a compound of formula (I) wherein R<1> represents alkyl and R<2> represents an acid-labile protecting group, by the reduction of a compound of formula (II) wherein R<1> and R<2> are as hereinbefore defined and R<3> represents a suitable leaving group. Compounds of formula (I) are useful in the synthesis of mevalonic acid derivatives.

Description: "DERIVATIVES OF PYRAN" THIS INVENTION relates to a new process for the preparation of intermediates for use in the preparation of pharmaceuticals, intermediates made by that process, and pharmaceuticals prepared from those intermediates. The intermediates preparable by the process of the present invention are the compounds of general formula I hereinafter depicted wherein R represents a straight- or branched-chain alkyl group containing from 1 to about 4 carbon atoms, preferably methyl or 2 isopropyl, and R represents an acid-labile protecting group, preferably a triphenylmethyl group. The compounds of formula I are key intermediates in a multi-stage reaction sequence which permits.the stereospecific preparation of analogues of mevalonic acid in previously known processes described, for example, by Rosen et a_l, J. Org. Chem., 1984, 49, 3994-4003 and 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. 07/230038 and 07/302389. It will be understood that, in a multi-stage process for the preparation of mevalonic acid derivatives both the yield in each stage, and the stereoselectivity, are of great importance if the overall process is to produce useful yields of stereochemically pure final product. The process of the present invention allows the intermediates of general formula I to be prepared in good yield and stereoselectivity. Reduction of the epoxy grouping in general formula II by the new process leads to the -hydroxy compound rather than the corresponding 3-hydroxy compound. The process also yields the 4α-hydroxy compound rather than the corresponding 4β-compound. 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 hypercholesterolaemic and hyperlipoproteinaemic states, atherosclerosis and associated conditions. The new process of the present invention comprises the reduction of compounds of general formula II hereinafter depicted, wherein R 1 and R2 are as 3 hereinbefore defined and R represents a suitable leaving group, for example a group of the general formula R 4SO.,-, wherein R4 represents an alkyl or aryl 3 group, for example R represents a ^toluene- sulphonyloxy or, preferably, ethanesulphonyloxy, group. The reduction is preferably carried out by means of an alkali metal borohydride derivative, preferably of the general formula M(R BH, wherein M represents an alkali metal, e.g. sodium, potassium or, preferably, lithium, the symbols R may be the same or different, and each represents a straight- or branched chain alkyl group containing from 1 to about 4 carbon atoms, preferably ethyl. The reaction is preferably carried out in an ethereal medium, for example in tetrahydrofuran, near or below the ambient temperature, for example from -10 to +20°C. At least 2 equivalents of the said borohydride derivative should be used, preferably about 4 to about 8, e.g. about 6 equivalents. The reaction should preferably be carried out in dry conditions, under an inert atmosphere. The reaction mixture is then worked up in a conventional manner, for example. by careful treatment with an aqueous solution of an alkali metal hydroxide, e.g. sodium hydroxide, followed by careful treatment with aqueous hydrogen peroxide solution, followed by extraction with a suitable solvent, e.g. diethyl ether, optionally followed b chromatography. According to a further feature of the present invention, compounds of formula I 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 Tatsuta et _1, Bull. Chem. Soc. Jpn., 61, 2525-2530 (1988). OH The following Example illustrates the present invention. The Nuclear Magnetic Resonance (NMR) spectrum was conducted in solution in CDC1 3 and the chemical shifts are given in ppm with tetra ethylsilane as reference. The following abbreviations are used:- "s" means "singlet", "d" means "doublet", "dd" means "doublet of doublets" and "m" means "multiplet". EXAMPLE 1 A stirred solution of 3α,4α-eρoxy-5β-methane- sulphonyloxy-6α-methoxy-2β-triphenylmethoxymethyl- tetrahydropyran (2.5g) in dry tetrahydrofuran (70ml) was treated, dropwise over a period of one hour, with a solution of lithium triethylborohydride in dry tetrahydrofuran (1.0M; 30ml) under a dry nitrogen atmosphere, maintaining the temperature at or near -5°C. The cooling bath was then removed and the reaction mixture was stirred at the ambient temperature overnight under dry nitrogen. The reaction mixture was then treated, dropwise over 10 minutes, with aqueous sodium hydroxide solution (3M; 65ml) at 5°C. The mixture was stirred for 5 minutes and then it was treated, dropwise over a period of one hour, at -5°C. with aqueous hydrogen peroxide solution, and the mixture was stirred for a further two hours. The mixture was then extracted with diethyl ether (4x150ml). The combined extracts were washed with water (2x100ml) and then with saturated aqueous sodium chloride solution (100ml), dried over magnesium sulphate and carefully concentrated iin vacuo to give a colourless oil (4g). This oil was subjected to chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (l:3v/v), to give 4α-hydroxy- 6α-methoxy-2β-triphenylmethoxymethyltetrahydropyran (1.4g), m.p. 98-99°C. [NMR:- ,7.48; m,7.36; d,4.90; m,4.20; m,4.05; d,3.60; s,3.45; dd,3.25; dd,3.05; m,1.5-1.6; m,1.7-1.9].

Claims: CLAIMS 1. A process for the preparation of a compound of general formula : wherein R 1 represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms and R 2 represents an acid-labile protecting group, which process comprises the reduction of a compound of general formula : wherein R 1 and R 2 are as hereinbefore defined and R 3 represents a suitable leaving group. 2. A process according to claim 1 wherein R 1 represents a methyl or isopropyl group. 3. A process according to claim 1 or 2 wherein R 2 represents a triphenylmethyl group. 4. A process according to claim 1, 2 or 3 wherein R 3 represents a group of the general formula R S0 3 -, wherein R 4 represents an alkyl or aryl group. 5. A process according to claim 4 wherein R 3 represents a p-toluenesulphonyloxy or methanesulphonyloxy group. 6. A process according to any one of the preceding claims wherein the reduction is effected by means of an alkali metal borohydride derivative. 7. A process according to claim 6 wherein the alkali metal borohydride derivative is of the general formula M(R 5 ) 3 BH, wherein M represents an alkali metal and the symbols Ϊ~ may be the same or different and each represents a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms. 8. Use of a compound of formula I as defined in claim 1 for the preparation of a mevalonic acid derivative.

Inventors: PITCHEN PHILIPPE, SMITH CHRISTOPHER, PITCHEN, PHILIPPE, SMITH, CHRISTOPHER
Applicants: RHONE POULENC RORER SA, RHONE-POULENC RORER S.A.
Application year: 1991
Main classification: C07H15
IPC codes: C07C51, C07C59, C07H15, C07H19