The method of obtaining tylosin

 

(57) Abstract:

The invention relates to a method for producing a drug that belongs to the macrolide group of antibiotics designed to treat a number of infectious diseases of animals. Describes how to obtain tylosin, including the production of salts of tylosin, characterized in that for receiving tylosin base for injectable salt tylosin is subjected to reaction with bases, the precipitate filtered and washed with water. The technical result - obtaining the target product, sufficiently pure for use in injectable forms a simple way from the available salts tylosin. 2 C.p. f-crystals.

The invention relates to a method for producing a drug that belongs to the macrolide group of antibiotics designed to treat a number of infectious diseases of animals.

Known biochemical methods of obtaining tylosin, which lies in the cultivation of a producer on a nutrient medium, followed by separation of tylosin from the culture fluid by extraction [Cm. Pat. NRB N 20697, IPC C 12 D 9/16; U.S. Pat. EPO N 0045157, IPC C 07 H 17/08; U.S. Pat. USA N 4362881, IPC C 07 D 313/00].

However, from the culture fluid select the first antibiotic. For the preparation of injectable form of tylosin is required in the form of a Foundation, as the shelf life and therapeutic efficacy of solutions of salts of tylosin is very limited [British Pharmacopoeia (Vet), 1993, p. 45]. Tylosin-base obtained directly from the culture fluid, becomes suitable for the preparation of injection solutions only after time-consuming and expensive clean-up, which determines its high cost compared with salts tylosin [Aksenov, I. A. Tylosin: Production and application of microbiological products industries. Survey information. - M.: UNISANTE Minmemory USSR, 1988. - Vol. 2, S. 28].

The closest in technical essence is a method for tylosin in which the culture fluid is subjected to extraction with butyl acetate, then hold reextraction tylosin in an aqueous solution of any acid, after removal of excess acid antibiotic solution concentrate, dried and receive tylosin in the form of water-soluble salts. [Makujina A. M. and other Production and use of tylosin for veterinary purposes. Survey, series 6. - M., 1984, S. 12].

Tylosin obtained by this method unsuitable for the preparation of injection is njection forms a simple way from the available salts tylosin.

The problem is solved by the synthesis of tylosin base of the salt exchange reaction with the base, the precipitate filtered and washed with water.

The reaction is carried out in aqueous medium at temperatures from room temperature up to 50oC by adding 0.5-1 M solution of a base in water to aqueous salt solution tylosin to pH of 8.6 to 8.8 or simultaneously with stirring in a small amount of water, 0.5-1 M solution of the base in water and concentrated aqueous salt solution tylosin. In the latter case, during the reaction maintain the pH of the medium from 7.5 to 8.6. After adding the total amount of salt tylosin pH was adjusted to 8.6 to 8.8. The reaction is carried out in a period of time from 20 minutes to 10 o'clock

The method is as follows. To obtain tylosin base can be used, for example, phosphate or tylosin tartrate obtained by known methods, for example, as in the prototype. Salt is subjected to reaction with a base, such as NaOH or KOH. Precipitated white precipitate tylosin base is filtered off, washed with distilled water and wet dissolve in hot propylene glycol. The resulting concentrate determine the content of tylosin base known methods, such as HPLC, after which it is prepared from injectionit 92-98% tylosin base (depending on the content of the basic substance in the original salt tylosin), meets the requirements of purity of the drug for injection forms. Output tylosin base from 90% to quantitative.

Example 1

In a solution of 3.5 kg (3,53 mol) of tylosin tartrate in 30 l of dist. water for 20 minutes under stirring was added 1 M aqueous KOH to pH in the reaction mixture of 8.8. The reaction was performed at 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 l), then was dissolved in 10 l of propylene glycol. Output tylosin base 97%.

Example 2

Into a solution of 35 g (0,037 mol) of tylosin phosphate in 30 ml of dist. water for 20 minutes under stirring was added 1 M aqueous KOH to pH in the reaction mixture of 8.8. The reaction was performed at 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 ml), then dissolved in 10 ml of propylene glycol. Output tylosin base 95%.

Example 3

In a solution of 3.5 kg (3,53 mol) of tylosin tartrate in 30 l of dist. water for 10 h under stirring was added 1 M aqueous NaOH to pH in the reaction mixture of 8.6. The reaction was performed at 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 l), then was dissolved in 10 l of propylene glycol. Output tylosin base 93%.

Example 4

In a solution of 3.5 kg (3,53 Mooi mixture of 8.6. The reaction was performed at 50oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 l), then was dissolved in 10 l of propylene glycol. Output tylosin base 92%.

Example 5

20 l SW. water under stirring were added simultaneously 1 M aqueous solution of NaOH and a solution of 3.5 kg (3,53 mol) of tylosin tartrate in 6 l of dist. water. Adding reagents were such a rate that the pH of the reaction mixture was 7,50,05, and the reaction time is 40 minutes After adding the whole amount of a solution of tylosin tartrate pH brought to 8.8. The reaction was carried out at a temperature of 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 l), then was dissolved in 10 l of propylene glycol. Output tylosin base 92%.

Example 6

20 l SW. water under stirring was added a 3 M aqueous solution of KOH and a solution of 3.5 kg (3,53 mol) of tylosin tartrate in 6 l of dist. water. Adding reagents were such a rate that the pH of the reaction mixture was 8,80,05, and the reaction time is 40 minutes After adding the whole amount of a solution of tylosin tartrate pH brought to 8.8. The reaction was carried out at a temperature of 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 l), then was dissolved in 10 obavljale simultaneously 1 M aqueous solution of KOH and the solution (0,037 mol) of tylosin phosphate in 6 l of dist. water. Adding reagents were such a rate that the pH of the reaction mixture was 8,3 of 0.05, and a reaction time of 2 hours After adding the whole amount of a solution of tylosin phosphate pH brought to 8.8. The reaction was carried out at a temperature of 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 ml), then dissolved in 10 ml of propylene glycol. Output tylosin base 95%.

Example 8

Into a solution of 35 g (0,0353 mol) of tylosin tartrate in 0,30 l SW. water for 20 minutes under stirring was added 5 M aqueous methylamine to pH in the reaction mixture of 8.8. The reaction was performed at 20oC. the precipitation tylosin base was filtered off, washed with dist. water (3x5 l), then was dissolved in 0,10 l propylene glycol. Output tylosin base 92%.

1. The method of obtaining tylosin, including the production of salts of tylosin, characterized in that for receiving tylosin base for injectable salt tylosin is subjected to reaction with bases in aqueous medium at a temperature from room temperature up to 50oC and pH 7.5 to 8.8, the precipitate is filtered off and washed with water.

2. The method according to p. 1, characterized in that add 0.5 - 5 M solution of the base in water to aqueous salt solution tylosin to pH of 8.6 to 8.8 during the presentations simultaneously into the water, in the reaction support pH of the reaction mixture to 7.5 and 8.6.

 

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4 tbl, 1 ex

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