DD297808A5 - METHOD OF ISOLATING TETRACYCLINE DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the separation of tetracyclines from reaction solutions. It was found, surprisingly, that a sulfosalicylic acid surrogate, which in addition to 60 to 70% sulfosalicylic acid contains 20 to 35%, sulfuric acid and about 5 to 10% water in a certain Reaktionsfuehrung the sulfonation of salicylic acid, the treat the tetracyclines in at least the same, z. T. even better quality and yield, as pure sulfosalicylic acid. {Process; Insulation; Cleaning; tetracycline derivatives; sulfosalicylic acid}

Description

The invention relates to a process for the separation of tetracycline from reaction solutions. The tetracyclines to be separated are active antibiotics or intermediates for their production.

In the processes for the preparation of tetracyclines, they generally accumulate in complex reaction mixtures. to Isolation and purification precipitates the products by salt formation with an acid with which the tetracyclines in the Reaction mixture form insoluble salts. Use as acids found e.g. Perchloric acid, toluenesulfonic acid, sulfosalicylic acid, hydriodic acid, hydrochloric acid. (E.g. DE-OS 2164840, DE-OS 2117442, DE-OS 2131 945) The salts formed by the use of perchloric acid are known to be explosive because of the tendency of perchlorates Disintegration can only be handled with extreme care, toluene sulfonic acid is only available in solutions with low water content

can be used, since the toluene sulfonates have a considerable solubility in water.

For deposition with hydrochloric acid, the product must usually be deposited as an amphoteric substance, since a number of Disturb reaction byproducts. The same applies to hydriodic acid, which is also very costly. The for the Deposition of particularly favorable sulfosalicylic acid, which also from dilute solutions, a deposition of tetracyclines in

high yields is possible, is a very expensive input product, as in their preparation, the separation of the

Sulfuric acid requires very energy intensive process.

The object of the invention is a process for the separation of tetracyclines from reaction solutions, which has the advantages of the deposition of sulfosalicylates without causing the high cost of sulfosalicylic acid.

The object of the invention is to provide a process for the isolation of tetracycline derivatives as sulfosalicylates, which causes lower material costs.

Surprisingly, it has been found that a sulfosalicylic acid crude product resulting from the sulfonation of salicylic acid in a specific reaction procedure and containing 20 to 35% sulfuric acid and about 5 to 10% water in addition to 60 to 70% sulfosalicylic acid precipitates the tetracyclines in at least the same amount, eg. even better quality and yield than pure sulfosalicylic acid. Further, it has been found that in the sulfosalicylic acid crude product all of the water formed in the sulfonation of salicylic acid is contained, while the filtrate of the sulfosalicylic acid crude product contains only sulfuric acid and small amounts of unreacted salicylic acid and, after addition of fresh salicylic acid and addition of the sulfuric acid again for the next batch sulfosalicylic acid can be used.

The reuse of the filtrate is unlimited. According to the invention, the recovery of the sulfosalicylic acid crude product which can be used for the tetracycline precipitation takes place in such a way that salicylic acid is concentrated in excess. Sulfuric acid enters, heated with stirring to temperatures between 365K to 400K, cooled and filtered off the crystallized Sulfosalizylsurerurerohprodukt. The filtrate is treated with conc. Sulfuric acid to the initial volume of the first batch added used for the subsequent approach and proceeded in the same way. The molar ratio of salicylic acid to sulfuric acid may be 1: 4 to 1:10, but a molar ratio of 1: 7 is optimal. The optimal temperature is 385K. Due to the low energy and technological complexity and the use of cheap large-scale chemical products, the cost of the precipitant in the production of Tetracyclinantibiotika be reduced by about 2 orders of magnitude. The following exemplary embodiments explain the method according to the invention.

example 1

1.a) Preparation of sulfosalicylic acid crude product

2.76kg of salicylic acid are added in 7.61 conc. Added sulfuric acid (or mother liquor + sulfuric acid) and heated with stirring, the salicylic acid goes into solution. At about 365K, the crystallization begins. Continue to warm to 385K, cool to room temperature with stirring, and centrifuge.

6.1 kg of sulfosalicylic acid crude product of the following composition are obtained Sulfosalicylic acid ~ 66% Sulfuric acid ~ 28%

Water 6%.

The filtrate of the sulforsalicylic acid crude product is supplemented with fresh sulfuric acid to 7.61 supplemented for the next batch.

b) Metacyclln-sulfosalizylate from a Metacyclln containing Lösu..g

177g 11 a-chloro-5-hydroxytetracycline-6,12-h "3miketal hydrochloride were dehydrated in 500ml anhydrous hydrogen fluoride at 268K, distilled off about 250ml hydrogen fluoride and the residue diluted with 620ml methanol with 100ml water and 17.5ml 37% Hydrochloric acid and a solution of 87.5 g of sodium dithionite in 350 ml of water was added and ?. Hours stirred.

After filtration, a solution of 132 g of sulfosalicylic acid crude product (obtained after Be.spiel I.Zusammensetzung: 66% sulfosalicylic acid, 28% sulfuric acid, 6% water) in 600 ml of water within one hour was added to the resulting metacyclin solution, one hour at 278K nachgerülirt the reaction product filtered off, washed with acetone and dried. This gives 193.5 g (83.3% of theory) Methacyclinsulfosalizylat.

2. Metacyclin sulfosalicylate from a solution containing Metacyclln

680 g 11 a-chloro-5-hydroxytetracycline-6,12-hemiketal hydrochloride are dehydrated by known methods and dehalogenated directly in the reaction solution diluted with methanol.

The reaction mixture is filtered and a solution of 635g Sulfosalizylsäurerohprodukt according to Example 1 (66% sulfosalicylic acid) in 3.81 water within one hour was added, stirred for 2 hours, finally at about 275 K. It is filtered, washed with acetone and dried. This gives 88 g (89.7% of theory) of pure Metacyclinsulfosalizylat.

3. a-Doxycyclin sulfosalizylate from a hydrogenation solution

24 g of metacyclin hydrochloride in 400 ml of methanol are hydrogenated in the presence of Wilkinson catalyst in the usual way. The hydrogenation solution was rapidly added at room temperature with a solution of 20g Sulfosalizylsäurerohprodukt (65% sulfosalicylic acid) in 800ml of water, stirred for 4 hours at room temperature and 2 hours at 280 to 285K, filtered off with suction, washed with acetone and dried. 27.3 g (78% of theory) of α-doxycycline sulfosalicylate are obtained which contains only traces of β-doxycycline and other by-products.

4. a-Doxycycline sulfosalicylate from a hydrating solution

33.6 g of metacyclin hydrochloride are hydrogenated. With a solution of 28 g sulfosalicylic acid crude product (prepared analogously to Example 1, composition: 65% sulfosalicylic acid, 29% sulfuric acid, 6% water) in 1.11 water, 39.1 g (80% of theory) of pure a-Doxycyclinsulfosalizylat.

Claims (4)

1. A process for the isolation of tetracycline derivatives as sulfosalicylates, characterized in that one uses for the precipitation of the tetracycline sulfosalizylate from the reaction solutions Sulfosalizylsäurerohprodukt, which from salicylic acid and sulfuric acid in a molar ratio 1: 4 to 1:10 by heating auf365K to 400K subsequent cooling and Filtration was obtained and still contains 20 to 35% sulfuric acid. 2. The method according to claim 1, characterized in that salicylic acid and sulfuric acid, in particular in a molar ratio of 1: 7 used to obtain the Sulfosalizylsurerohproduktes and heated to a temperature of preferably 380K to 390K. 3. The method according to claim 1, characterized in that the sulfosalicylic acid crude product preferably contains 26 to 30% sulfuric acid. 4. The method according to claim 1, characterized in that is precipitated as tetracycline sulfosalizylata-Doxycyclin sulfosalisylat and metacyclin sulfosalicylate.