CS239442B1 - Process for preparing 1,4-benzenediol-2,3,5-trimethyl-4-acetate - Google Patents

Abstract

The invention relates to a method for preparing 1,4-benzenediol-2,3,5-trimethyl-4-acetate by partial deacetylation of 1,4-benzenediol-2,3,5-trimethyl-1,4-diacetate in aqueous methanol by the action of alkali metal carbonate in the presence of a reducing agent at a temperature of 25 to 60 °C for 0.5 to 2 hours; 1,4-benzenediol-2,3,5-trimethyl-4-acetate is an important intermediate in the production of some synthetically prepared drugs. The invention finds application in the pharmaceutical industry, e.g. in the production of Trimepranol.

Description

The invention relates to a process for the preparation of 1,4-benzenediol-2,3,5-trimethyl-4-acetate of formula I

OCOCH ₃

CH3 - x ^ --CH,

CH, (I)

OH partial desacetyláciou 1,4-benzenediol, 2,3,5-trimethyl-1,4 ^_-diacetétu of formula II * _OCOCH3

CH ₃ CH ₃ CH ₃ (II)

OCOCHj

In the synthesis of some drugs, it is necessary to use 1,4-benzenediol-2,3,5-trimethyl-4-acetate as an intermediate. This is prepared by partial desacetylation of the corresponding diacetate with an aqueous methanolic ammonia solution. Partial desacetylation of 1,4-benzenediol-2,3,5-trimethyl-1,4-diacetate with aqueous methanolic ammonia solution is perfectly reproducible only with accurate temperature control of the reaction mixture, since the hydrolysis constant is temperature-dependent.

In a strong alkaline environment, the second acetyl group is also partially hydrolyzed, forming a hydroquinone, from which brown undefined products are formed by the action of air oxygen, so it is necessary to work in an inert gas environment. Isolation of the pure product is also not easy. The reaction solution was concentrated to remove excess methanol and the product was precipitated with water, extracted, concentrated and crystallized. In this process, two mother liquors are formed which need to be treated. The reaction yields are also not satisfactory and do not exceed 78%.

PodTa čs. AO č. 183,338, 1,4-benzenediol-2,3,5-trimethyl-4-acetate is prepared by alcoholysis of 1,4-benzenediol-2,3,5-trimethyl-1,4-diacetate by boiling with absolute methanol from * present, The disadvantage of this process is the increased energy consumption, since the reaction is carried out by boiling in methanol and the reaction mixture is separated from the azeotropic mixture of methyl acetate - methanol.

Another disadvantage is the use of absolute methanol and the use of sodium methoxide, which must be prepared from sodium metal and methanol. A device with a rectification column installed is required to carry out the reaction, which increases the cost of constructing the device. The yield of the reaction was 88.5%.

The aforementioned drawbacks are overcome by the process for the preparation of 1,4-benzenediol-2,3,5-trimethyl-4-acetate (I) according to the invention, which is characterized in that 1,4-benzenediol-2,3,5-trimethyl-1 4-diacetate (II) is subjected to partial desacetylation in an aqueous methanolic medium with an alkali metal carbonate, preferably potassium carbonate, in the presence of a reducing agent at 25 to 60 ° C for 0.5 to 2 hours; wherein the molar ratio of diacetate II, alkali metal carbonate and reducing agent is 1: 0.2 to 0.4: 0.05 to 0.2.

The resulting 1,4-benzenediol-2,3,5-trimethyl-4-acetate is isolated by pouring the reaction mixture into chilled water and filtering or diluting the reaction mixture with water, cooling and filtration. Reaction yields reach 92% without treatment of the mother liquors. The reaction proceeds under mild conditions, without great energy requirements and reproducible. The reducing agent present, sodium bisulfite, sodium dithionite or sodium bisulfite, prevents the formation of brown undefined oxidation products which would contaminate the end product; The 1,4-benzenediol-2,3,5-trimethyl-4-acetate prepared according to the invention does not require purification and can be used for the next reaction.

The following examples illustrate the process of the invention

EXAMPLE

47.2 g (0.2 mol) of 1,4-benzenediol-2,3,5-trimethyl-1,4-diacetate are dissolved in 150 ml of methanol by heating to 45-50 ° C. After cooling to 35 ° C, 2.5 g (0.013 mol) of sodium bisulfite and a solution of 6.9 g (0.05 mol) of potassium carbonate in 25 ml of water are added. The resulting suspension was stirred at 35-40 ° C for 1 hour.

After this time, the reaction mixture was cooled to 20 ° C and 250 mL of water cooled to 5 ° C was added, leaving 1,4-benzenediol-2,3,5-trimethyl-4-acetate to precipitate.

The suspension was stirred at 5 ° C for 1 hour. The recovered crystal is filtered off with suction and thoroughly washed with cold water until the filtrate is neutral (pH 7) and is dried at a temperature of up to 50 ° C. The reaction yields 31.8 g of crystalline product containing 99.8% 1,4-benzenediol-2,3,5-trimethyl-4-acetate, m.p. 108-111 ° C. 82% yield.

Example 2

47.2 g (0.2 mol) of 1,4-benzenediol-2,3,5-trimethyl-1,4-diaeetate are dissolved in 150 ml of methanol by heating to 45-50 ° C. After cooling to 35 ° C, 2.5 g (0.013 mol) of sodium bisulfite and a solution of 7.4 g (0.07 mol) of anhydrous sodium carbonate in 25 ml of water are added. The resulting suspension was stirred at 35-40 ° C for 1.5 hours.

After this time, the reaction mixture was cooled to 20 ° C and 250 mL of water cooled to 5 ° C was added, leaving 1,4-benzenediol-2,3,5-trimethyl-4-acetate.

The suspension was stirred for 1 hour at 5 ° C. The recovered crystal is filtered off with suction and thoroughly washed with cold water until the filtrate is neutral (pH 7) and dried at a temperature of up to 50 ° C.

The reaction yields 32 g of a crystalline product containing 99.6% 1,4-benzenediol-2,3,5-trimethyl-4-acetate, m.p. 108-111 ° C.

Example 3

47.2 g (0.2 mol) of 1,4-benzenediol-2,3,5-trimethyl-1,4-diacetate are dissolved in 150 ml of methanol by heating to 45-50 ° C. 5 g (0.026 mol) of sodium bisulfite and a solution of 9 g (0.065 mol) of potassium carbonate in 15 ml of water are added to the resulting solution after cooling to 35 ° C. The resulting suspension was stirred at 35-40 ° C for 1 hour.

After this time, the reaction mixture was cooled to 20 ° C and 250 mL of water cooled to 5 ° C was added, leaving 1,4-benzenediol-2,3,5-trimethyl-4-acetate. The suspension was stirred for 1 hour at 5 ° C. The recovered crystal is filtered off with suction and thoroughly washed with cold water until the filtrate is neutral (pH 7) and dried at a temperature of up to 50 ° C. The reaction yielded 35.9 g of a crystalline product containing 100% 1,4-benzenediol-2,3,5-trimethyl-4-acetate, m.p. 104-107 ° C. 92.5% yield.

Claims (1)

239442 4 SUBJECT OF THE INVENTION Process for preparing 1,4-benzenediol-2,3,5-trimethyl-4-acetate of formula I (X) by partial desetaethylation of 1,4-benzenediol-2,3,5-trimethyl-1,4-diacetate of formula II CH 3 ocooxo X / CH 3 OCOCH, (II) in alkanoic water-methanolic medium, characterized in that 1.4 -benzenediol-2,3,5-trimethyl-1,4-diacetate in aqueous methanol containing 5 to 25% by volume of water, preferably 10% by volume, is subjected to partial desethylation by the action of an alkali metal carbonate, preferably potassium carbonate , in the presence of a reducing agent, a temperature of 25 to 60 ° C for 0.5 to 2 hours, wherein the molar ratio of 1,4-benzenediol-2,3,5-trimethyl-1,4-acetate, alkali metal carbonate and reducing agent used is is 1: 0.2 to 0.4: 0.05 to 0.2. Severografia, n. P., MOST Price 2,40 Kcs