CS208352B1 - Method of racemization of the l-alfa-acetamido-beta-hydroxy-p-nitropropiophenone - Google Patents

Description

The invention relates to a process for the racemization of L-α-acetamido-p-hydroxy-p-nitropropiophenone of the formula

NHCOCH2

N ₂ - (2 -) --CH ₂ OH to D, N -acetamido-β-hydroxy-p-nitropropiophenone.

As is known, in the final stages of the synthesis of the antibiotic chloramphenicol, an important intermediate intermediate DL-2-amino-1-p-nitrophenyl-1,3-propanediol is obtained, which is separated by crystallization into optical antipodes, of which only the D-forms are used. The L-form is waste that cannot be directly recovered, for example by racemization and re-separation into optical antipodes.

One possibility of utilizing the waste L-form is to convert it back, preferably in the form of the N-acetylderivative, to L-α-acetamido-β-hydroxy-p-nitropropiophenone (L-ketone) by oxidation with various reagents and under different conditions. Said L-ketone can be easily racemized to the corresponding D, L-form, which is already one of the intermediates of conventional chloramphenicol synthesis.

Racemization of the L-ketone in the D, L-form is best carried out in a mildly alkaline medium, such as the racemization of similar compounds using sodium acetate in acetic acid (J. Kollonitsch, A. Hajos, Acta Chim. Acad. Sci. Hung. 8) , 271, 1955) or with a carbonate or sodium bicarbonate in an aqueous-alcoholic medium at room temperature, for a reaction time of 1 to 2 days, with yields of 80 to 95% (USSR Patent No. 108,299). M. Nagawa (Takamine Kenkyusko Nempo 10, 11, 1958) racemizes the L-ketone by boiling with dichloroethane in a yield of 46%. Furthermore, racemization in methanol by treatment with ammonium hydroxide in 88% yield [Japanese Pat. No. 11756 (60)] and finally in a 5% aqueous solution of sodium bicarbonate at 20 ° C in 95% yield. (M. Portelli, Ann. Chim. (Rome) 53, 1447, 1963). However, neither of these processes satisfies the requirements for the highest yield, short reaction time, least effort and the highest quality of the final product.

The aforementioned drawbacks are eliminated by the method of racemization of La-acetamido-p-hydroxy-p-nitropropiophenone to the D, La-acetamido-p-hydroxy-p-nitropropiophenone according to the invention, which consists in carrying out 2 to 3 mol of water 0.8 to 1.2 moles of alkanol and 1 to 4 carbon atoms, preferably ethanol, 2.8 to 5.5 moles of halogenated aliphatic hydrocarbon having 1 to 2 carbon atoms, preferably dichloromethane, by treatment with 0.2 to 0 3 moles of a weak inorganic or organic base, such as alkali metal carbonates, acid carbonates or acetates, preferably sodium bicarbonate, based on 1 mol of the starting L-ketort, at a temperature of 20 to 45 ° C, preferably 35 to 40 ° C .

Crude La-acetamido-P-hydroxy-pnitropropiophenone, formed by oxidation of L-threo-2-acetamido-1-p-nitrophenyl-1,3-propanediol, as a solution in a halogenated aliphatic hydrocarbon having 1 to 2 atoms, is used as starting material for racemization. carbon, preferably dichloromethane, forming part of the racemization environment.

This arrangement, which is expediently linked to the known oxidation process, makes it possible to simply and economically return waste which has not been recovered to production and thus to obtain economically interesting amounts of chloramphenicol.

Further details of the production method according to the invention can be seen from the following examples.

Examples

Example 1

In a reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 90 g of L-threo-2 'amino-1β-nitrophenyl-1,3-propanediol (L-base) (with a dry matter content of 81.1%) and 270 ml of water are added, The reaction mixture is heated to 60 DEG C. and 90 ml of acetic anhydride are added dropwise with stirring at such a rate that the temperature of the reaction mixture does not exceed 65 DEG. After quantitative completion of the acetylation, the reaction mixture is cooled to 35 ° C, 270 ml of dichloromethane, 27.6 g of potassium bromate and 5 ml of 50% hydrobromic acid are added. With vigorous stirring, oxidation takes place quantitatively in about 70 minutes. The reaction mixture was cooled to 15-20 ° C and neutralized with 25% ammonium hydroxide solution while stirring and cooling so that the temperature did not exceed 25 ° C and the pH of the mixture was 7.0-7.5. After cooling the reaction mixture to 10 ° C, the upper aqueous layer was separated and 10 ml of water, 17 ml of ethanol and 5.7 g of acidic acid were added to the lower dichloromethane layer containing La-acetamido-β-hydroxy-p-nitropropiophenone (L-ketone). sodium carbonate. The mixture thus prepared was heated to 40 ° C with stirring under reflux for 1 hour. 165 ml of dichloromethane were then distilled off over 3 hours to complete the racemization. Verification shall be carried out by measuring the optical rotation.

Claims (2)

SUBJECT A method for racemizing L-α-acetamido-β-hydroxy-p-nitropropiophenone of the formula NHCOCH-5 0 ₂ N —CCHCH ₂ 0H sample size. The reaction is complete when the optical rotation is zero. After complete racemization, the reaction mixture is cooled to 5 ° C and the product is filtered off with suction, washed with 10 ml of methylene chloride and dried. The yield was 63.5 g, i.e. 73.2%, based on the starting L-base. Mp 156-161 ° C, (? X) d = 0 ° (c = 2, e = 2, dimethylformamide). Example 2 In a 1000 ml reaction vessel equipped with a stirrer, reflux condenser and thermometer, 110 g of L-ketone (96.7% solids content), 85 ml of dichloromethane, 20 ml of water, 25 ml of ethanol and 10 g of sodium bicarbonate are added. Heat the mixture in a water bath at 40 ° C. The course of racemization is monitored by measuring the optical rotation of the samples. After 2 hours, the racemization is complete. The reaction mixture is cooled to 0 ° C, the product is filtered off with suction, washed with dichloromethane and water until the alkaline reaction is washed with water and dried. Yield 99.1 g (i.e. 93.2% based on the starting L-ketone). M.p. Mp 156-161 ° C, (a) n = 0 (c = 2, e = 2, dimethylformamide). Example 3 Racemization of L-ketone at 35 ° C and reaction time of 4 hours under otherwise the same conditions as in Example 2 gave the racemate in 93.8% yield. Example 4 Racemization of L-ketone at 20 ° C and a reaction time of up to 2 days, under otherwise the same conditions as in Example 2, gave the racemate in 95% yield. Example 5 Racemization of L-ketone in larger amounts of dichloromethane (200 mL), under otherwise the same conditions as in Example 2, gave the racemate of better quality (mp 158-162 ° C) and with larger crystals but in lower yield (90.7%) . Example 6 Racemization of L-ketone with more water (70 mL), under otherwise the same conditions as in Example 2, afforded the racemate in higher yield (94.2%) but less pure (mp 152-158 ° C). Example 7 Racemization of L-ketone with more ethanol (70 mL) under otherwise identical conditions to Example 2 gave the racemate in 89% yield. OF THE INVENTION for D, La-acetamido-3-hydroxy-p-nitropropiophenone, characterized in that it is carried out in a medium of a mixture of 2 to 3 moles of water, 0.8 to 1.2 moles of C 1 -C 4 alkanol, preferably ethanol; 5.5 moles of a halogenated aliphatic hydrocarbon having 1 to 2 carbon atoms, preferably dichloromethane, by treatment with 0.2 to 0.3 moles of a weak inorganic or organic base, such as alkali metal carbonates, acid carbonates or acetates, preferably sodium bicarbonate, based on 1 mol of the starting L-ketone, at a temperature of 20 to 45 ° C, preferably at 35 to 40 ° C. 2. The process according to claim 1, wherein the starting material for racemization is crude N-acetamido-3-hydroxy-p-nitropropiophenone formed by oxidation of L-threo-2-acetamido-1-pnitrophenyl-1,3- propanediol, in the form of a solution in a halogenated aliphatic hydrocarbon having 1 to 2 carbon atoms, preferably dichloromethane, forming part of the environment for racemization.