CS231441B1 - A method of treating a partially decomposed reaction of a mixture after reduction of D, L-2-ecetamido-3-hydroxy-1- (4-nistrophenyl) -1-propanesone - Google Patents

Abstract

The invention relates to the production of the broad-spectrum antibiotic chloramphenicol. It addresses the processing of the reaction mixture after Meerwein, Ponndorf and Verley reduction with recycling of 2-propanol.

Description

(54) A process for treating a partially quenched reaction of a mixture after reduction of D, L-2-ecetamido-3-hydroxy-1- (4-nitrophenyl) -1-propsone

BACKGROUND OF THE INVENTION The present invention relates to the production of a broad spectrum antibiotic chloramphenicol.

It solves the reaction treatment of the mixture after Meerwein, Ponndorf and Verley reduction with 2-propanol recycling.

One of the production steps for the synthesis of the broad-spectrum antibiotic chloramphenicol is the Ueerwein, Ponndorf and Verley reduction of DL-2-acetamido-3-hydroxy-1- (4-nitrophenyl) -1-propanone (I) to D, L-threo-2-acetamido- 1- (4-nitrophenyl) -1,3-propanediol (II).

The reduction is carried out with a mixture of triisopropoxy- and chlorodiisopropoxy-alene in anhydrous 2-propanol. Acetone is distilled continuously from the reaction mixture. After the distillation was complete, the mixture was quenched with hydrochloric acid.

. The amount of acid supplied is 4 to 6 times the equivalent of aluminum. A portion of aqueous 2-propanol and hydrochloric acid is then distilled off. After heating, acetamidodiol II is deacetylated to give D, L-threo-2-amino-1- (4-nitrophenyl) -1,3-propanediol hydrochloride (III) which is isolated by crystallization.

Another known method of treating the previously specified reaction mixture after ketone I reduction is based on partial decomposition of the product with an aqueous solution of 2-propanol, thereby forming an insoluble compound of acetamidodiol II, aluminum and 2-propanol in the reaction medium.

The compound is isolated and the acetamidodiol II is then liberated by treatment with an aqueous or aqueous-alcoholic base solution. After removal of the aluminum hydroxide, acetamidodiol is isolated by crystallization.

The hydrochloride III is prepared from acetamidodiol II in a conventional manner. Efforts to simplify this procedure result in modification by omitting separation of the acetamidodiol II compound, the clay and 2-propanol.

Another difference was that, unlike the previous method, the absolute 2-propanol was obtained not by filtration but by distillation. The distillation was terminated by the same treatment as in the previous case.

Despite indisputable advantages, the procedures outlined have a number of drawbacks. Treatment of the reaction mixture by decomposition with hydrochloric acid makes it impossible to absolutely disperse the 2-propanol which has been removed. Moreover, it does not address the purification of the isolated product.

The decomposition of the reaction mixture with an aqueous solution of 2-propanol leads to the recycling of 2-propanol in the production, but it presents new problems with aluminum hydroxide separation.

These drawbacks are overcome by the process of the present invention. According to the invention, the acetamidodiol II, aluminum and 2-propanol compound formed by quenching the reaction mixture after Meerwein, Ponndorf and Verley reduction of ketone I with aqueous 2-propanol is treated with a sulfuric or hydrochloric acid solution to form a neutral aluminum complex.

This releases not only acetamidodiol II, but also the previously bound 2-propanol, which is distilled off from the reaction mixture and basified in the next batch. Acetamidodiol II is then precipitated from the cooled reaction mixture and worked up in the usual manner.

The treatment of the reaction mixture after the reduction according to the invention brings a number of advantages. On the one hand, it introduces 2-propanol recycling into production. There is no difficulty in processing the aluminum hydroxide and the alumina complex can be further utilized in another industry. On the other hand, it also guarantees high purity of the product without reducing the yield. Waste water purity benefits are also negligible. With all the advantages indicated, it is easy to implement the invention under operating conditions.

The following examples illustrate the invention and its effects.

23H41

He did

An axis of a 21-liter three-necked flask equipped with a reflux condenser, stirrer, water lesion and thermometer was charged with 44 g of aluminum shavings, 5 g of carbon tetrachloride, 50 ml of 2-propanol and 0.1 g of mercury chloride.

The mixture was heated in a water bath to 60 ° C. Once the aluminum had begun to dissolve in the reaction mixture, 35 g of carbon tetrachloride and 750 ml of 2-propanol were added in portions. After all the aluminum had dissolved, the reflux condenser was replaced with a descending condenser and 200 g of ketone I was introduced into the flask.

The reaction mixture was further heated at 50 ° C for 4 hours while the aveton formed was vacuum distilled. A total of 170 ml of acetone and 2-propanol were distilled off. The mixture was then cooled to 20 ° C and quenched with 230 mL of 80% aqueous 2-propanol.

Then the mixture was heated to 84 ° C and the distilled 2-propanol was distilled. 270 ml of 97% 2-propanol were obtained. 615 ml of 0.95 N hydrochloric acid were poured into the flask at 20 ° C with stirring.

After stirring for 4 hours, the precipitated acetamidodiol II was filtered off. 142 g (71%) of acetamidodiol II (m.p. 59-164 ° C) were obtained. The mother liquors were concentrated by distilling off 350 ml of 20% 2-propanol to precipitate ballasts which were removed by filtration through carboraffin.

From the purified solution, crystallization at 10 ° C yielded 34 g (17%) of acetamidodiol II (m.p. 158-62 ° C).

Example 2

The same amount of substances was introduced into the same apparatus as in the previous case, and ketone I was reduced in an analogous manner.

After cooling to 20 ° C, the flask was poured into 615 mL of a 95 N sulfuric acid solution. The mixture was heated to boiling. The precipitated aluminum complex was filtered off. 345 ml of 85% aqueous 2-propanol was distilled off from the filtrate.

After cooling to 20 ° C, acetamidodiol II started to precipitate. 72 g (86%) of acetamidodiol II (m.p. 150-162 ° C) were obtained.

Claims (2)

OBJECT OF THE INVENTION Process for working a partially decomposed reaction mixture after reduction of D, L-2-ecetemido-3-hydroxy-1- (4-nitrophenyl) -1-propenone, characterized in that the compound D, L-threo-2- aceteaido-1- (4-nitrophenyl) -1,3-propanediol, aluminum and 2-propanol formed by decomposition of the reaction began after the Meerwell, Ponndorf and Verley reduction of the starting hydroxymethylketone with aqueous solution and 2-propanol, treated with aqueous sulfuric or hydrochloric acid, the concentration of acid used is 0.1 to β N, and the amount of acid supplied to the reaction mixture is equivalent to 0.1 to 2.8% of the amount of aluminum contained in the reaction mixture, so that the aluminum contained in the reaction mixture becomes neutral and released D, L-threo-2-acetemido-1- (4-nitrophenyl) -1,3-propanediol and 2-propanol are removed from the reaction mixture by 20 to 00%, e.g. by distillation, and then from the reaction mixture. of the mixture eliminates acetaaidodiol, which optionally isolated, preferably by filtration or centrifugation. 2. The process of claim 1 wherein the compound of the aluminum, D, L-thrso-2-acetamido -, - (4-nitrophenyl) -1,3-propanediol and 2-propanol is decomposed by acid at 0 [deg.] C.