CS209253B1 - Process for producing racemic 1- (p-nitro) -1-amino-1,3-propanediol - Google Patents

Abstract

The invention relates to a process for the preparation of racemic ' 1-(p-nitrophenyl)-2-amino-1,3-propanediol (IV), an important intermediate in the synthesis of chloramphenicol. This compound has hitherto been prepared by hydroxy- | methylation of 2-acetamino-p-nitroacetophenone (I) and by the Meerwein-Ponndorf reduction of the resulting 2-hydroxymethyl-2-acetamino-p-nitroacetophenone (II):

Description

The invention relates to a process for the preparation of racemic 1- (p-nitrophenyl) -2-amino-1,3-propanediol (TV), an important intermediate of chloramphenicol synthesis. This compound has hitherto been produced by hydroxy- methylates of 2-acetamino-p-nitroacetophenone (I) and Meerwein-Ponndorf reduction

2-hydroxymethyl-2-acetamino-p-nitroacetophenone (II):

NHCOCH. i j

NHC0CH

AND

n ° _2/1 /

CH ₂ OH / IV /

Meerwein. The Ponndorf reduction of II has still been carried out as a separate operation by the action of aluminum isopropylate or, more preferably, a mixture of isopropylate and aluminum chlorisopropylate. By close monitoring of the course, it was found that the reduction of the keto group of compound I did not proceed quite smoothly. In addition to the previously found in the reaction mixture

The presence of 2-acetamino-p-nitrophenylacrylophenone (III) produced by dehydration was also detected by thin-layer chromatography, which was undoubtedly formed by dehydroxymethylation of II. It has been verified that this reaction proceeds very easily, since the dehydroxymethylation product can be detected by thin layer chromatography after several hours of standing at room temperature for a solution of Π in methanol. In addition, it has been found that: unlike substance II, substance I is very difficult to reduce by the Meerwein-Ponndorf reaction.

The discovery of such significant differences between the rates of the individual reactions, i.e., reduction of I, its hydroxymethylation to II, and its subsequent reduction to give racemic base IV, prompted the development of a process for producing racemic 1- (p-nitrophenyl) -2-amino. -1,3-propanediol by hydroxymethylation

2-acetamino-p-nitroacetophenone and reduction of the resulting 2-hydroxymethyl-2-acetamino-p-nitroacetophenone with aluminum isopropylate; A mixture of isopropylate and aluminum chlorisopropylate according to the invention, characterized in that the hydroxymethylation and reduction are carried out simultaneously in one operation.

The reduction may be carried out using formaldehyde polymers, preferably paraformaldehyde, in isopropanol at the boiling point of the reaction mixture or in the same medium in a closed vessel at 105-115 ° C.

In carrying out the process according to the invention, it is generally carried out by first preparing a solution of aluminum chlorisopropylate in isopropanol, to; with acetaminoketone I and paraformal-; dehyd or trioxymethylene. First, the mixture after I

Even atmospheric pressure is heated to boiling or autoclave to a temperature of about 110 ° C, after completion

Claims (3)

j SUBJECT Process for the preparation of racemic 1- (p-nitrophenyl) -2-amino-1,3-propanediol by hydroxymethylation 2-acetamino-p-nitroacetophenone and reduction of the resulting 2-hydroxymethyl-2-acetamino-p-nitroaceto- phenone with aluminum isopropylate or a mixture of isopropylate and aluminum chlorisopropylate, characterized in that the hydroxymethylation and reduction are carried out simultaneously in the one operation. isopropa is slowly distilled off under vacuum. nol, the residue is quenched with dilute hydrochloric acid and the precipitated hydrochloride IV is filtered off with suction. Al ₂ O ₃ thin layer chromatograms taken during the reaction clearly show the loss of starting material I and the steady increase in racemic base IV. Since the spot corresponding to substance II is barely noticeable and never exceeds 5%, this also demonstrates a considerable difference in the regularity of the reactions I -> II <II - »IV. ₇ ...... J _________.________ and method according to the invention is advantageous in particular also in that the reaction substances to substances is not carried out as _Π; a separate operation, thereby eliminating the loss of Π due to its partial solubility in aqueous; furthermore, a considerable amount of auxiliaries (methanol, dichloroethane) used in hydroxymethylation are saved, and finally the entire chloramphenicol synthesis is shortened and the capacity of the production equipment is increased. Examples 1. A solution chlorisopropylátu aluminum pri- \ pravenéhoz 15 ghliníku 0.1 gHgCl ₂ 1.25 gCCl ₄ 12.5 g of POCl ₃ and 450 ml of isopropanol are added, and 50 g are added. Of 2-acetamino-p-nitroacetaminophenone-para-formaldehyde and the mixture was boiled under stirring for 2 hours. The isopropanol is then distilled off under reduced pressure within 30 minutes and the thick residue is decomposed! ί 1 hour heating to 70 ° C with 220 ml conc. hydrochloric acid and 100 ml of water. The crude hydrochloride IV, precipitated by cooling the mixture to -5 [deg.] C., is filtered off with suction, recrystallized with the addition of 2 g of tartaric acid and quenched with 2% of ammonia by aqueous ammonia. Release! The converted racemic base IV is aspirated and dried at 50 ° C. Yield 29.6 g (62.74%). 2. Place the reaction mixture prepared as in Example 1 in an autoclave and heat at 110 ° C for 2 hours. After cooling, the mixture was poured into a distillation vessel and isopropanol was distilled off with stirring for 30 minutes. Proceed as in Example 1. | Yield: 30.6 g (65%). OF THE INVENTION 2. The process according to claim 1, wherein the reaction is carried out using polymers of formaldehyde, preferably paraformaldehyde, in isopropanol at the boiling point of the reaction mixture. j 3. The process of claim 1 wherein the reaction is carried out in an isopropanol environment in a sealed vessel at 105-115 ° C.