PROCESS FOR 2-DEOXYGLUCOSIDES

Abstract: The invention provides a process for the preparation of methyl tri-O-acetyl-2-deoxyglucoside by the reaction of tri-O-acetyl-D-glucal with methanol in the presence of hydrogen bromide or a source thereof. alpha -Methyl tri-O-acetyl-2-deoxyglucoside is especially useful as an intermediate in the preparation of pharmaceutically useful mevalonic acid derivatives.

Description: DESCRIPTION - PROCESS FOR 2-DEOXYGLUCOSIDES THIS INVENTION relates to a new process for the preparation of intermediates useful in the preparation of pharmaceuticals, to their use in the preparation of said pharmaceuticals, and to pharmaceuticals prepared from said intermediates. The new process of the present invention, which has not been described specifically hitherto, is for the preparation of methyl tri-0-acetyl-2-deoxyglucoside hereinafter depicted in formula I from tri-O-acetyl-D- glucal hereinafter depicted in formula II. The process is carried out by reaction with methanol in a suitable solvent selected from, for example, chloroform, dichloromethane, toluene, ethyl acetate, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidinone, acetone, and ethers, e.g.. tetrahydrofuran and t-butyl methyl ether, and, more especially, acetonitrile and 1,2-dimethoxyethane, and in the presence of a catalyst comprising hydrogen bromide or a source thereof, for example hydrobromic acid or triphenylphosphine hydrobromide. Preferably the molar proportion of catalyst to starting material of formula II is at least 10%, preferably from 20% to 50% or more. The reaction is conveniently carried out under an inert atmosphere, e.g. nitrogen, and at or near room temperature. The compound of formula la is a key intermediate in a 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 use of compounds prepared by the process of the present invention in a reaction sequence which permits the preparation of analogues of mevalonic acid, and analogues of mevalonic acid prepared thereby, are further features of the present invention. 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. Examples of such mevalonic acid analogues are described, for example, in the specifications of 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. The process of the present invention has good stereospecificity, i.e. the product contains a high ratio of α-methyl tri-0-acetyl-2-deoxyglucoside, hereinafter depicted in formula la, to /3-methyl tri-0-acetyl-2- deoxyglucoside, hereinafter depicted in formula lb, typically a ratio of up to 10:1 or more. The compound of formula la may be separated by the application or adaptation of known methods, for example by chromatography, or, especially when the product contains at least 90% of la, it may be used as such. The α-methyl tri-0-acetyl-2-deoxyglucoside ano er is the preferred product because currently it is of greater utility in the preparation of pharmaceuticals than is the 0-methyl tri-0-acetyl-2-deoxyglucoside anomer. The compound of formula la may be hydrolysed by the application or adaptation of known methods to give α- methyl 2-deoxyglucoside, hereinafter depicted in formula III, which may thereafter be 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. By the term "known methods" as used in this specification is meant methods used heretofore or known in the literature. I The following Examples illustrate the present invention. In the Examples, "% cat" denotes the molar proportion of catalyst to compound of formula II in the initial reaction mixture, "TPHB" denotes triphenyl- phosphine hydrobromide, "aq.HBr" denotes 48%w/w hydrobromic acid, "DCM" denotes dichloromethane, "MeCN" denotes acetonitrile, "DME" denotes 1,2-dimethoxy- ethane, "% yield" denotes the percentage yield of compound of formula I based upon the starting material of formula II, and "α:β" denotes the ratio of the anomers in the product (determined by examination of the nuclear magnetic resonance spectrum of the crude product in deuterochloroform) . EXAMPLES 1 to 10 In Examples 1 to 10 the catalyst was added to a 10%w/w solution of tri-O-acetyl-D-glucal (4mmoles) and methanol (βmmoles) in the solvent at room temperature under nitrogen and stirred overnight at room temperature. The solution was then concentrated and the product was subjected to chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (l:3v/v) to give a mixture of α-methyl tri-O-acetyl-2-deoxyglucoside and β-methyl tri-O- acetyl-2-deoxyglucoside in the ratio stated in the table. *In Example 10 the product was a complex mixture. EXAMPLE 11 % cat catalyst solvent % yield α:β : 20 HBr MeCN 93 5:1 A 25%w/w solution of hydrogen bromide in 6 mmoles of methanol was added to a 10%w/w solution of tri-O-acetyl-D-glucal (4mmoles) in acetonitrile at room temperature under nitrogen and stirred overnight at room temperature. The solution was then concentrated and the residue was partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with water, dried over magnesium sulphate, and concentrated in vacuo to give a mixture of α-methyl tri-O-acetyl-2-deoxyglucoside and β-methyl tri-O- acetyl-2-deoxyglucoside in the ratio 5:1.

Claims: CLAIMS 1. A process for the preparation of methyl tri- O-acetyl-2-deoxyglucoside of the formula: which comprises the reaction with methanol of a compound of the formula: in the presence of a catalyst comprising hydrogen bromide or a source thereof. 2. A process according to claim 1 in which the methyl tri-0-acetyl-2-deoxyglucoside product comprises at least 90% of α-methyl tri-O-acetyl-2-deoxyglucoside of the ormula: 3. A process according to claim 1 or 2 in which the reaction is carried out in, as solvent, chloroform, dichloromethane, toluene, ethyl acetate, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidinone, acetone, tetrahydrofuran or t-butyl methyl ether. 4. A process according to claim 1 or 2 in which the process is carried out in, as solvent, acetonitrile or 1,2-dimethoxyethane. 5. A process according to any one of the preceding claims in which the reaction is carried out in the presence of, as catalyst, hydrobromic acid or triphenylphosphine hydrobromide. 6. A process according to any one of the preceding claims in which the molar proportion of catalyst to starting material of formula II is at least 10%. 7. A process according to claim 6 in which the molar proportion is from 20% to 50%. 8. A process according to any one of the preceding claims in which the reaction is carried out under an inert atmosphere and at or near room temperature. 9. A process for the preparation of α-methyl 2- deoxyglucoside of the formula which comprises the hydrolysis of a compound of the formula: 10. Use of a compound of the formula la depicted in claim 9 in the preparation of mevalonic acid analogues. 11. Use of a compound of the formula III depicted in claim 9 in the preparation of mevalonic acid analogues.

Inventors: MIOSKOWSKI CHARLES, PITCHEN PHILIPPE, MIOSKOWSKI, CHARLES, PITCHEN, PHILIPPE
Applicants: RHONE POULENC RORER LTD, RHONE-POULENC RORER LIMITED
Application year: 1991
Main classification: C07H15
IPC codes: C07H15