PROCESS FOR PREPARING BETA-HYDROXY-BETA-METHYLGLUTARIC ACID

Abstract: Described in a novel process for preparing ß-hydroxy-ß-methylglutaric acid by treating 3-methyl-1,3,5-pentanetriol in aqueous media with a permanganate salt.

Description: Process for Preparing ss-Hydroxy-ss-Methylglutaric Acid i-Rydroxy-ss-methylglutaric acid (HMG) is well established as a hypolipidemic and hypocholesterolemic agent (Yusufi et al, Atherosclerosis,20, 517(1974) and U.S. Patent 3,629,449), The synthesis of this biologically important compound has been primarily accomplished by (1) oxidation of diallylmethyl carbinol or 3-hydroxy-3-methyl-hex-5-enoic acid with ozone and hydrogen peroxide (Klosterman et al, J. Am. Chem. Soc. 76, 1229(1954); Biochemical Preparations, 6, 25(1958); Tschesche et al, Ann. der Chemis, 631, 61(1960) and (2) a Reformatsky reaction between ethyl acetoacetate and ethyl bromoacetate (dams et al, J.-Am. Chem. Soc. 75, 2377(1953). Both of the above described synthetic methods for the preparation of H14G embrace difficult. multi-step procedures, require complicated purification schemes and produce low yields. The present invention overcomes the disadvantages of the prior art by providiny a simple one step synthesis of L'IC from a readily available starting material. Use of the procedure described herein permits large scale synthesis of the HMG at very low cost. Summary of the Invention The present invention relates to an improved process for the production of 6-hydroxy-B-methylglutaric acid (HMG). More particularly, the present invention relates to a pro cess for preparing HMG which comprises oxidizing 3-methyl1,3,5-pentanetriol. This reaction proceeds schematically as follows: EMI2.1 For the oxidation an oxidizing agent is used which converts primary alcohols into the corresponding carboxylic acids. The preferred oxidizing agents are permanganate salts. The reaction is preferably carried out in an aqueous medium. In accordance with a preferred embodiment of the present invention, ss-hydroxv-ss-methylglutaric acid (HMG) is prepared by treating 3-methyl-i,3,5-pentanctriol with a permanganate salt selected from the group consisting of sodium permanganate and potassium permanganate in an aqueous medium. The reaction is carried out in aqueous media which is preferably neutral or alkaline. The use of an acidic inedium is a disadvantage because the yield of HMG is lower and the product is somewhat more difficult to isolate. Strongly acidic reaction conditions should be avoided due to the susceptibility of HMG to dehydration. The reaction temperature employed herein can range from about 10 0C to 110 0C with a temperature range of 30 0C to 450C being preferred. A reaction time of approximately three hours is satisfactory, but the reaction time can vary from 10 minutes to several days depending on the scale of the reaction. The mole ratio of permanganate to triol can range from 3:1 to 5:1 with a ratio of 4:1 being preferred. The reaction product is recovered by conventional means. For example, insoluble manganese dioxide is removed from the reaction mixture by filtration or centrifugation. The filtrate or centrifugate containing the product is then acidified to a pH of 1-2 with concentrated HC1. The resulting acidified filtrate or centrifugate is then concentrated to yield the acid residue which is further purified by recrystallization from a suitable solvent, such as ethyl acetate or acetonitrile. The yields of HMG produced by the process of the present invention are excellent, i.e. yields in excess of 40% are routinely obtained. The term "aqueous media" as used herein preferably refers to water, however minor amounts of water miscible solvents that do not interfere with the oxidation reaction may be used in combination with water. 3-Methyl-1,3,5-pentanetriol utilized herein is commer cially-vailable. The following specific description is given to illustrate the present invention. EXAMPLE A 2 liter reaction vessel is charged with 800 mQ of water, 240 g potassium permanganate (1.52 mole) and 3 mt l9N sodium hydroxide. The resulting reaction mixture is stirred for approximately 10 minutes to dissolve most of the permanganate and the temperature is adjusted to approximately 250C. While the resulting solution is further agitated at room temperature, 50 mQ of a solution of 54 g of 3-methyl-1,3,5-pentanetriol (0.4 mole) in 150 mQ of water is added. After the addition of 50 mQ of the triol solution the temperature will rise to about 350C. After approximately 10 minutes, the remaining triol solution is added dropwise over a period of 15 minutes. During the addition, the temperature is maintained at 400 to 430C by cooling the reaction vessel in an ice bath. After all of the triol solution has been added, the exothermic reaction will continue for about ona hour. During this time, and thereafter for a period of 3 hours, the temperature is maintained at 4 Thereafter, the reaction mixture is heated to 800C for approximately 10 minutes and then allowed to cool to room temperature. The reaction mixture is filtered and the filter cake is suspended in 200 mQ of water. The suspension is stirred well and then filtered. The filtrates are combined and acidified to pH 1.5 with concentrated hydrochloric acid. The acidified filtrate is then dried under reduced pressure at 60 to 650C to obtain a dry salt cake. The above-obtained salt cake is extracted with approximately 200 mQ of acetone with the salt being removed from by filtration. Thereafter, the cake is extracted again with two 50 mQ portions of acetone. The acetone extracts are combined and dried under reduced pressure to obtain a stiff syrup which is dissolved in approximately 100 mt of boiling acetonitrile. Four grams of anhydrous magnesium sulfate and 1 gram of activated carbon are added to the hot solution which is then filtered. The resulting product is allowed to crystallize with stirring at room temperature for 3 hours. The resulting slurry is stirred with cooling to OOC. The crystallized product is recovered by filtration, washed with ethyl acetate cooled to -200C and dried under reduced pressure at 45 C to yield 26-28 grams of S-hydroxy-ss-methylglutaric acid, m.p. 1050C- 1080C, Yield 40 - 42%.

Claims: What is claimed is: 1. A process for preparing 8-hydroxy-B-methylglutaric acid which comprises oxidizing 3-methyl-1,3,5-pentanetriol. 2.. A process as defined in Claim 1 wherein said oxidizing is carried out with a permanganate salt. 3. A process as defined in Claim 2 wherein said perman ganate salt is selected from the group consisting of potassium permanganate and sodium permanganate. 4. A process for preparing ss-hydroxy-ss-methylgiutaric acid which comprises oxidizing 3-methyl-1,3,5-pentanetriol in aqueous media with a permanganate salt selected from the group consisting of potassium permanganate and sodium permanganate. 5. A process as defined in Claim 4 wherein said oxidizing is carried out at a temperature of from about 700C to 0 110 C. 6. A process as defined in Claim 5 whereinthetemperature is from about 30 0C to 45 0C. 7. A process as defined in Claim 4 wherein the molar ratio of salt to triol is in the range of 3:1 to 5:1. 8. A process as defined in Claim 4 wherein said aqueous media areneutral or alkaline.

Inventors: METZNER, ERNEST KURT
Applicants: AMERICAN HOECHST CORPORATION
Application year: 1982
Main classification: C07C51
IPC codes: C07C51