JPS58105938A - Manufacture of bata-hydroxy-beta-methylglutaric acid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides β-hydroxy-β-methylglutar II
(IIMG).

More specifically, the present invention provides a method for producing HMG, comprising:
3-Methyl-1,5,5-pentanetriol is treated in an aqueous medium with a permanganate salt selected from the group consisting of potassium permanganate and sodium permanganate, and then β-hydroxy- β
- HMG characterized by recovering methylglutaric acid
Relating to a manufacturing method.

β-hydroxy-β-methylglutaric acid (HMG)
is well established as a hypolipidemic and cholesterol-lowering agent (Yusufi et al.
o cis (Atheroscleroais), 2
0.517 (1974) and U.S. Patent No. 3,529,
Specification No. 449].

The synthesis of this biologically important compound was accomplished by (1) the oxidation of diallylmethylcarbinol or 3-hydroxy-3-methyl-hex-5-enoic acid with ozone and hydrogen peroxide (Losterman et al. J, Am , C
hem, 8oc, 76.1229 (1954), B
iochemical preparations,
6 25 (1958), Tschesches et al. K. Ann, der Ohemig, 631.61 (19
60)) and (2) Leformadsky reaction between ethyl acetoacetate and ethyl bromoacetate [Adams et al., J. Am. Ohem, Boa, 75.237
7 (1953)).

) Both of the above synthetic methods for the production of IMG involve laborious multi-step operations, require complex purification mechanisms, and result in low yields.

The present invention overcomes the shortcomings of the prior art by providing a simple one-step synthesis of HMG from readily available starting materials. Using the procedures described herein, large-scale synthesis of HMG is possible at a very low cost.

According to the present invention, β-hyroxy-β-methylglutarate (mMG) is obtained by converting 3-methyl-1,,3,5-pentanetriol into a compound selected from the group consisting of sodium permanganate and potassium permanganate. It is produced by treatment with permanganate.

This reaction is preferably carried out in an aqueous medium that is neutral or alkaline. The use of acidic media is disadvantageous. This is because the yield of IIIMG is lower and the isolation of the product is more difficult. Strongly acidic reaction conditions must be avoided as HMG is susceptible to dehydration.

Reaction temperatures as used herein can range from about 10°C to 110°C, and from 60°C to 40°C.
A temperature range of 5° C. is preferred. A reaction time of about 6 hours is sufficient, but this reaction time can vary from 10 minutes to several days depending on the scale of the reaction.

The molar ratio of permanganate to triol is between 6:1 and 5.
:1, with a ratio of 4:1 being preferred.

The reaction products are 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 diluted with concentrated salt to fJ″1
Acidified to 1 to 2. The resulting acidified filtrate or centrifuge is then concentrated to yield an acid residue that is further purified by recrystallization from a suitable solvent such as ethyl acetate or acetonitrile.

The yield of M() produced by the method of this @kei is excellent. For example, yields of greater than 50 inches are usually obtained.

The term "aqueous medium" as used herein preferably refers to water, however, trace amounts of water-miscible solvents that do not interfere with the oxidation reaction may be used in combination with water.

3-methyl-1°6.5- utilized herein
Pentanetriol was obtained from Kuraray Sozolenich Gaku Co., Ltd., Tokyo, Japan.

The following specific description is provided to enable those skilled in the art to more clearly understand and practice the present invention. This description should not be considered as limiting the scope of the invention;
They should be considered merely illustrative and representative.

The reactor of Example 21 was charged with 80 Qd of water, 240.9 (1,52 moles) of potassium permanganate, and 191! hydroxide)
Charge 13 um 3 yxl. The resulting reaction mixture is stirred for about 10 minutes to dissolve most of the permanganate, and the temperature is then adjusted to about 25°C. The resulting solution was further stirred at room temperature to dissolve 3-methyl-L 3,5-pentanetriol (0.4 mol) in water 1501
Add 50 wLt of solution of 5411. Triol solution 5
After addition of 01, the temperature rises to about 35°C. After about 10 minutes, the remaining triol solution is added over a period of 15 minutes. During this addition, the temperature is maintained at 40° C. to 43° C. by cooling the reactor in a water bath.

After all the triol solution has been added, the reaction continues to be exothermic for approximately 1 hour. During this time and for the next 3 hours the temperature was 43
kept at ℃. The reaction mixture was then stirred at 80°C for about 10 minutes.
and then cooled to room temperature.

The reaction mixture was filtered and the filter cake was dissolved in 200 g of water.
Suspend in M1. The suspension is thoroughly stirred and then filtered. Combine this filtrate and add concentrated salt to pH 1,
Acidify to 5. The acidified filtrate was then dried under reduced pressure at 60°C to 65°C to obtain a dry salt mass.

The salt mass obtained above is extracted with about 200 ml of acetone and the salt is removed by filtration. This mass is then further extracted twice with acetone 501.

The acetone extracts are combined and dried under reduced pressure to obtain a stiff syrup, which is then heated with boiling acetonitrile for about 1 hour.
001111C dissolve. 4 g of anhydrous magnesium sulfate and 1 g of activated carbon are added to the hot solution and then filtered. The product obtained is crystallized at room temperature with stirring for 3 hours. The resulting slurry is stirred while being cooled to 0°C.

The crystallized product was collected by filtration, washed with ethyl acetate cooled to -20°C and then dried under reduced pressure at 45°C to give β-hydroxy-β-methylglutar W1261 with a melting point of 105°C to 108°C. or 28
Obtain Ii.

Agent Asamura Hao 4 other people

Claims (9)

[Claims] (1) A method for producing β-hydroxy-β-methylglutaric acid, which comprises oxidizing 3-methyl-1,3,5-pentanetriol. (2) the oxidation is carried out using permanganate;
A method according to claim 1. (3) The method of claim 2, wherein the permanganate is selected from the group consisting of potassium permanganate and sodium permanganate. (4) oxidation of 3-methyl-1,5,5-pentanetriol with a permanate selected from potassium permanganate and sodium permanganate in an aqueous medium, β- A method for producing hydroxy-β-methylglutaric acid. 5. The method of claim 4, further comprising: (5) recovering β-hydroxy-β-methylglutaric acid from the aqueous medium. 6. The method of claim 4, wherein the oxidation is performed at a temperature of about 10°C to 110°C. (7) The method of claim 6, wherein the temperature is about 30°C to 45°C. (8) The method according to claim 4, wherein the molar ratio of ester to triol is within the range of 6:1 to 5:1. (9) The method according to claim 4, wherein the aqueous medium is neutral or alkaline.