BG61266B1 - Method for the preparation of20-dehydro-20-deoxy-20-=(cis-3,5-dimethylpiperidine-1-il)-desmycosin - Google Patents

Abstract

The method is applied for the preparation of medicament forthe veterinary medicine. Desmycosin is condensed by3,5-dimethylpiperidine in the presence of sodium hyposulphate asreducer at 30 to 60?C. The20-dehydro-20-deoxy-(cis-3,5-dimethylpiperidin-1-il)-desmycosinproduced is isolated in dry and is extracted by organic solventswhich cannot mix with water, e.g. methylenechloride, at pH from7.5 to 10.5 and is desolvated by propyleneglycol under vacuum.Preservers and water are added until the production ofconcentrtates for the preparation of finished medicamentouspreparations.

Description

TECHNICAL FIELD

The invention relates to a process for the preparation of 20-dehydro-20-deoxy-20- (cis-

3,5-dimethylpiperidin-1-yl) -desmicosin, which is used in the pharmaceutical industry.

BACKGROUND OF THE INVENTION

The 20-aminosubstituted macrolide antibiotic derivative tylosin is used as a substance in the preparation of veterinary drug forms. Its antibacterial spectrum of activity encompasses gram-positive bacteria, Mycoplasma species, Pasteurella maltocida, Mycoplasma gallisepticum, P.multocida, Pasteurella haemolytica, etc., in which MICs range from 0.78 to 6.25 μg / ml. Its effectiveness against pasterologists has been demonstrated in vitro and in vivo.

A method is known for the preparation of 20dehydro-20-deoxy-20- (cis-3,5-dimethylpiperidin-1-yl) desmicosin by two-step chemical synthesis of desmicosin, in which desmicosin and 3,5-dimethylpiperidine are dissolved in acetonitrile, dehydrated with potassium carbonate and 95 + 97% formic acid in acetonitrile was added to the resulting solution. As a result of the Leuckart-Wallach reaction, 20-dehydro-20-deoxy-20 (3,5-dimethylpiperidin-1-yl) desmicosine is obtained. The reaction mixture was extracted with water at acidic pH, then isolated in dry form 20dihydro-20-deoxy-20- (cis-3,5-dimethylpiperidin-1-yl) desmicosin (EP 0240264).

A method is known in which tylosin is extracted with amyl acetate from a tylosin phosphate solution, reacted by heating with 3,5-dimethylpiperidine and formic acid in an amyl acetate solution, and then the resulting 20-dihydro-20-deoxy-20- (3,5-dimethylpiperidine- il) tylosin is hydrolyzed at pH 1.5 to

20-dehydro-20-deoxy-20- (3,5-dimethylpiperidin-1-yl) desmicosin (EP 0240264).

A method is known in which desmicosin is dissolved in dry methanol, cis-

3,5-dimethylpiperidine and cyanoborohydride. The solvent was evaporated in vacuo and the residue was extracted with phosphate buffer (pH 6.5 and 4.5) in the presence of ethyl acetate. The aqueous layer was extracted with ethyl acetate at pH 10, the organic phase was dried with magnesium sulfate and evaporated, yielding 20-dehydro-20-deoxy-20- (cis-3,5-dimethyl piperidin-1-yl) -desmicosin (EP 0262903).

The resulting 20-dehydro-20-deoxy-20 (cis-3,5-dimethylpiperidin-1-yl) desmicosin is dissolved in propylene glycol by known methods in known methods, stabilizers are added and the resulting solution is used for formulation.

The disadvantages of these methods are the multi-stage synthesis, which reduces the yield, the need to conduct the synthesis under anhydrous conditions; the use of expensive and toxic raw materials (eg sodium cyanoborohydride); environmental problems; the product is isolated in the dry state before being put into the dosage form.

It is an object of the invention to provide a process for the preparation of 20-dehydro-20deoxy-20- (cis-3,5-dimethyl-piperidin-1-yl) desmicosin in high yield and purity, in a simplified flow chart, in an aqueous medium without using toxic raw materials.

SUMMARY OF THE INVENTION

The problem is solved by a method in which a lower aliphatic alcohol or ketone and cis-3,5-dimethylpiperidine (1.0+ 1.1 Μ) are added to the aqueous solution of desmicosin at pH 7.0 + 8.0 (with 20% sulfuric acid), 30 min at +20 + 30 ° C. Sodium hyposulphite or sodium formaldehyde sulfoxylate hydrate (1 + 5 M) was added and stirred for 2 h at + 30 + 60 ° C. Adjust the pH of the solution to 9.7 + 10.2 with 20% sodium hydroxide, heat to +30 + 45 ° C, then allow 20-dehydro-20deoxy-20- (cis-3,5-dimethyl piperidin-1-yl) ) Desicosin should be isolated in a known dry manner. After the condensation was completed, instead of isolating the dry product, methylene chloride was added to the reaction mixture, the pH adjusted to 7.7 + 8.5 with 20% ammonia to extract the antibiotic. The methylene chloride layer was separated and the salt was triturated with propylene glycol. The methylene chloride is removed in vacuo (azeotropically separating the water and some of the propylene glycol). After analyzes and dilution to the required concentration with propylene glycol, a preservative and water are added to the solution of 20-dihydro-20-deoxy-20- (3,5-dimethylpiperidin-1-yl) desmicosin to obtain the dosage forms.

30 + 60% lower aliphatic alcohol (ethanol, propanol, propanol) or acetone is added to the desmicosin condensation with cis-3,5-dimethylpiperidine.

The advantages of the process according to the invention are that a process for the preparation of 20-dehydro-20-deoxy-20 (cis-3,5-dimethylpiperidin-1-yl) desmicosin in a high yield and purity has been devised according to a simplified flow chart , in aqueous medium without the use of toxic raw materials.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

The invention is illustrated by the following examples.

1. In a mixture of 50 ml of water and 50 ml of isopropyl alcohol dissolve 10 g of desmicosin (11.8 mmol, 11.50 g with a purity of 87%), add 1.50 g of 3,5-dimethylpiperidine (13 mmol, 98.2% purity; 85 and the pH of the mixture was adjusted to 7.8 with 20% sulfuric acid. The mixture was stirred for 30 min at + 25 ° C. 5.14 g of sodium hyposulphite (29.5 mmol) was added in two portions over 15 min and the solution was heated with stirring at + 50 ° C for 120 min. Cool to + 37 ° C and add 200 ml of sodium chloride-saturated water to the solution. Adjust the pH of the mixture to 10.2, stir for 90 min at +35 + 40 ° C. The crystals were filtered off, washed with 30 ml of water, heated to + 40 ° C, and dried in vacuo at + 50 ° C. 11.11 g of 20-dehydro-20-deoxy-20 (cis-3,5-dimethylpiperidin-1-yl) desmicosin (purity 85.43%) is obtained, yield 91.4% over desmicosin.

2. The culture fluid (2.9 L) obtained from the cultivation of Str.fradiae NA-34 containing 3.8 g / Ι desmicosin is extracted at pH 10.2 with 1 L butyl acetate. Re-extract with 2% phosphoric acid solution to pH 2. To the re-extract (45 ml) was added 55 ml of acetone, 1.50 g of 3,5-dimethylpiperidine (13 mmol, 98.2% purity, 5% cis) and the pH of the mixture was adjusted. to 7.9 with 20% phosphoric acid. 3.20 g of sodium formaldehyde sulfoxylate, hydrate (27.1 mmol, calculated at 100%) was added and the solution heated at + 50 ° C for 120 min. Cool to + 20 ° C, add 300 ml of water and 100 ml of methylene chloride. Stir for 15 min, then separate the layers. The methylene chloride was concentrated in vacuo to 1/5 of the volume, 40 ml of propylene glycol was added. The solution was concentrated to a volume of 35 ml. A propylene glycol solution of 20-dehydro-20-deoxy-20- (cis-

3,5-dimethylpiperidin-1-yl) desmycosin at a concentration of 270 860 mcg / ml and a purity of 83.87%, yield 92.4%. 1.9 ml of benzyl alcohol and pyrogen-free water were added to the solution to a volume of 47.4 ml.

Claims (3)

1. A process for the preparation of 20-dehydro20-deoxy-20- (cis-3,5-dimethylpiperidin-1 yl) desmycosin by condensation of desmycosin with cis-3,5-dimethylpiperidine in the presence of a reducing agent followed by crystallization and isolation, characterized is that the condensation process is carried out in aqueous medium in the presence of sodium hyposulphite at +30 + 60 ° C. 2. The method of claim 1, wherein after condensation the resulting 20-dehydro-20-deoxy-20- (cis-3,5 dimethylpiperidin-1-yl) desmycosin is extracted with a water-immiscible organic solvent at pH 7.5 10.5, desolvated with propylene glycol in vacuo and preservatives and water added to obtain concentrates for the preparation of medicaments. A method according to claims 1 and 2, characterized in that it is immiscible with