HU181620B - Process for the isolation of doxycycline-hydrochloride - Google Patents

Description

The present invention relates to a novel process for the preparation of a-6-deoxy-5-oxytetracycline hydrochloride (doxycycline hydrochloride) of formula (I). In therapy, the hydrochloride salt of doxycycline hemihydrate hemalcoholate is used. Doxycycline can be obtained from 5-oxytetracycline by chemical conversion in several steps. The final steps of the process are the dehalogenation of 11a-chloro-6-methylene-5-oxytetracycline (chloromethacycline) of formula II, wherein R is hydrogen or acyl, Hal is chlorine, and reduction of the 'exocyclic double bond. followed by separation of the doxycycline from the reaction mixture, generally in the form of its 5-sulfosalicylic acid salt, and purification thereof, followed by conversion with hydrochloric alcohol to the doxycycline hydrochloride. The process is described in J. Am. Chem. Soc., 85, 2643-2649 (1963) and in U.S. Patent 3,397,231.

Reduction of the compound of formula (II) results in significant amounts of isomers and degradation products, such as apo and anhydrotetracycline, unreduced 6-methylene-5-oxytetracycline (methacycline), p-6-deoxy-5-oxy tetracycline.

Α-6-Deoxy-5-oxytetracycline hydrochloride (doxycycline hydrochloride) is a broad-spectrum antibiotic that is active against Gram-positive and Gram-negative bacteria, salmonella, brucella, rickettsia and larger viruses. The α-isomer is most effective, so various methods are used for its pure preparation and removal of by-products.

For example, in U.S. Patent No. 3,397,231, sulfosalicylic acid is added to the reaction mixture after hydrogenation and the precipitated doxyclinic sulfosalicylate is recrystallized from anhydrous methanol by heating. The final product is obtained from the recrystallized salt by dissolving it in anhydrous ethanol containing at least 12 molar equivalents of hydrochloric acid and crystallizing the doxycycline hydrochloride hemihydrate hemalcohol from 4% to 10% water. The disadvantages of the method are that it requires the use of aggressive materials at high temperatures (solutions of hydrogen chloride in anhydrous alcohols), the use of special, very expensive equipment which often needs to be replaced due to the corrosion that occurs, and equipment. In addition, the quality of the target product does not meet the water solubility requirements; the product obtained has a solubility of only 1:50 (Example 2 of our description), while the required solubility is 1: 3. The product obtained by this method contains 5 to 8% impurity and is dark yellow to tan in color.

The method described in U.S. Patent 4,061,676 is an improved modification of the process described in U.S. Patent 3,397,231. According to the method, the apo and anhydrous impurities present in the reaction mixture are removed by acidifying the mixture with a concentrated aqueous solution of methanesulfonic acid, hydrochloric acid or sulfuric acid so that the final acid concentration is not more than 18%, and Store at 90 ° C. The resulting solution is treated with sulfonic salicylic acid to form doxycycline in the form of a poorly soluble sulfosalicylate. The sulfosalicylate thus obtained is converted into a doxycycline base in ethanol30 containing 10-50% water by addition of an equimolar amount of triethylamine, which is dissolved in aqueous hydrochloric acid and then added to a solution of 17.5% ethanolic hydrochloric acid. a final product. The disadvantage of this method is that the destruction of the apo and anhydrous impurities and the recovery of the final product are technologically difficult because they require the use of aggressive materials, such as high temperature solutions of 18% hydrochloric acid and ethanolic hydrogen chloride gas. The method does not provide a satisfactory separation of related impurities (methacycline and β-isomer); this is evidenced by the data in Example 8 of this description. Descriptions 1-7. Example 1 of this example lacks data on the methacycline and β-isomer content of the final product and intermediate. However, the results of repeating this method, which are shown in Table 1, show insufficient separation of related impurities.

Table 1

Results of Repeating the Method of U.S. Pat. No. 4,061,676 (Example 1)

β-isomer methacycline content with reference to α-isomer (%) reaction Mixtures Doxycycline sulphosaicylate 90:10 15-20: 8-10 The method also comprises recovering the doxycycline base, which conditions (pH 3.6-6.0) favor 4-epi-

dare to form. As a result, there is a risk of further contamination of the final product.

The object of the present invention is to simplify the technological process and improve the quality of the end product. We can achieve these goals in the following way.

Doxycycline is isolated from the mixture of related compounds in aqueous methanolic solution by reaction with p-toluenesulfonic acid; Doxycycline tosylate of formula C22H24N2Oe.HSO3C6H4.CH3OH.H2O is formed. The mixture of apo and anhydro derivatives is digested in an alkaline medium at pH 10-12 at 10-20 ° C. This reaction may be continued until the tosylate is formed or recrystallized. The final product is swallowed from doxycycline tosylate by reaction with hydrochloric acid in ethyl alcohol.

The method of the present invention is as follows.

After catalytic hydrogenation, p-toluenesulfonic acid in aqueous methanol is added to the reaction mixture, resulting in the formation of doxycycline tosylate. If the concentration of doxycycline in the mixture is not too high, the mixture may be slightly concentrated. If the catalytic hydrogenation is carried out in a different solvent, the reaction mixture is concentrated in vacuo and the residue is dissolved in aqueous methanol. Methanol containing 20-40% water is the optimum for recovering the tosylate. The doxycycline tosylate is then recrystallized and simultaneously subjected to the treatment necessary to destroy the apo and anhydro derivatives; the tosylate is dissolved in 70% aqueous methanol at a pH of 10-12. To the solution was added p-toluenesulfonic acid and hydrochloric acid

Until a pH of 1.5 to 1.8 is reached and the doxycycline tosylate is crystallized. The alkaline digestion may also be carried out immediately after the catalytic hydrogenation, before the addition of p-toluenesulfonic acid. The recrystallized doxycycline tosylate was dissolved in ethanol2 by the addition of 3 molar equivalents of concentrated hydrochloric acid. The final product precipitated by the addition of 7 molar equivalents of hydrochloric acid. The efficacy of doxycycline separation from the mixture according to the proposed method is illustrated in Table 2.

Table 2

Effectiveness of the process of the invention in recovering doxycycline from the reaction mixture

β-isomer methacycline content with reference to α-isomer (%) reaction Mixtures 90 10 Doxycycline tosylate 3-8 <2 Recrystallized tosylate <2 traces end product <1 traces

The salt of doxycycline with p-toluenesulfonic acid is not described in the literature. The rapid and selective degradation of the apo and anhydro compounds in alkaline media was also unknown. Based on previous knowledge, it was not expected that the recovery of doxycycline in the form of tosylate from the reaction mixture and the alkaline digestion of the apo and anhydro compounds would significantly improve the separation. Already during the conversion of doxycycline to tosylate, the related impurities can be separated, the apo and anhydro derivatives can be completely destroyed and the desired end product can be obtained directly from the doxycycline tosylate in very good quality.

The proposed method is illustrated by the following non-limiting examples:

Example 1

A) Recovery of doxycycline tosylate from the reaction mixture

(a) 400 ml of an aqueous solution of methanol containing the mixture obtained from the hydrogenation of la-chloromethacycline tosylate, namely:

16.4 g of α-6-deoxytetracycline, 14.5 g of β-6-deoxytetracycline and 1.6 g of methacycline, 10 g of p-toluenesulfonic acid are added. The solution was stirred at 5-7 ° C for 16-18 hours. The precipitated crystalline precipitate was collected, washed with methanol and dried. 17.3 g of yellowish crystalline product are obtained, containing 87% of 6-deoxytetracycline tosylate. The β-isomer content is 3% and the methacycline content is 2%. Yield 86.4% based on α-isomer.

b) The aqueous methanolic solution prepared in (a) is concentrated in vacuo to give a tar residue which is dissolved in 200ml of 70% aqueous methanol containing 10g of toluenesulfonic acid. The mixture containing crystals was stirred for 5 hours, the precipitate was filtered off, washed with methanol and dried. 18.9 g of yellowish crystalline product are obtained, containing 85% of 6-deoxytetracycline tosylate. The β-isomer content is 8% and the methacycline content is 2%. Yield 88% with respect to α-isomer.

c) Concentrate the aqueous methanolic solution prepared in a) under vacuum to obtain a tarry residue which is dissolved in 200ml of 70% aqueous methanol. A 10% sodium hydroxide solution is added until the pH is 10-12. 10 g of toluenesulfonic acid and concentrated hydrochloric acid are then added until the pH is 1.5-1.8. After 5 hours, the precipitate was filtered off. 17.6 g clear

-2181620 powder containing 92.3% of 6-deoxytetracycline tosylate. The β-isomer content is 8% and the methacycline content is 2%. Yield 88.5% based on α-isomer.

B) Recrystallization of doxycycline tosylate

(a) 18 g of doxycycline tosylate are suspended in 160 ml of 80% aqueous methanol. The suspension is adjusted to pH 10-12 with 10% aqueous sodium hydroxide solution. Then, 5 g of toluenesulfonic acid and concentrated hydrochloric acid are added until the pH is between 1.5 and 1.8. During the process, the temperature of the solution is maintained between 10-20 ° C. The mixture containing the crystals was stirred for 2 hours, then the precipitate was filtered off, washed with methanol and dried. 13.3 g of white crystals are obtained, containing 93% of 6-deoxytetracycline tosylate. The β-isomer content is 2% and traces of methacycline are present. Moisture content 2.6% (K. Fischer method), methanol content 5.4%. Yield 88%.

(b) Dissolve 18 g of doxycycline tosylate in 180 ml of 50% aqueous methanol at 68-70 ° C. To the resulting solution was added 5 g of toluene sulfonic acid and heating was continued for a further 45 minutes. The solution was cooled, stirred for two hours, and filtered. The precipitate was washed with methanol and dried. 13.15 g of doxycycline tosylate are obtained. β-isomer content below 3%, methacycline content below 1%. Moisture content 2.7%, methanol content 5.2%.

c) If the doxycycline tosylate obtained in Step Ac) is recrystallized as described in Ba), sodium hydroxide solution is added until the tosylate is dissolved (pH 7.0-7.7), followed by the addition of toluenesulfonic acid and Ba). .

d) If the doxycycline tosylate obtained in Step Ac) is recrystallized as described in Section Ba), the suspension of the tosylate is heated until it is completely dissolved, after which p-toluenesulfonic acid is added, the solution is cooled and proceeded as described in Section Bb). a.

C) Preparation of doxycycline hydrochloride from doxycycline tosylate

13 g of recrystallized doxycycline tosylate are suspended in 170 ml of ethyl alcohol. The suspension is heated to 70 ° C and concentrated hydrochloric acid is added with stirring until complete dissolution of the tosylate (~ 6 mL). The resulting solution was clarified with activated charcoal (0.9 g) and filtered. 14 ml of concentrated hydrochloric acid are added to the filtrate. The solution was cooled to room temperature and stirred for 2 hours. The precipitate is filtered off, washed on the filter with ethyl alcohol and dried. 8.25 g of doxycycline hydrochloride hemihydrate hemi-alcohol are obtained. The mother liquor was concentrated in vacuo after separation of the doxycycline hydrochloride.

To the concentrate was added 0.5 g of toluene sulfonic acid. After 16 hours, the precipitated crystals were filtered off. 1.9 g of doxycycline tosylate are obtained, which corresponds to the recrystallized doxycycline tosylate according to the quality determined on the basis of its α and β isomer content. Total yield 94.5%.

Example 2

Preparation of Doxycycline Sulfonic Salicylate - Repeat Example I of U.S. Patent 4,061,676

The aqueous methanolic solution of Example 1 (A) (a), containing 3.1 g of α-6-deoxytetracycline, 2.9 g of β-6-deoxytetracycline and 0.32 g of methacycline is evaporated in vacuo. The pellet was dissolved in a mixture of 43 ml of dimethylformamide and 15 ml of water. To the solution was added 27.5 ml of concentrated hydrochloric acid, heated to 68-70 ° C for 30 minutes. The solution was then cooled to 50 ° C and 12 g of sulfosalicylic acid and 35 ml of water were added. The crystallization material is kept at 5-10 ° C for 2 hours and then filtered. The precipitate was washed with 60% aqueous methanol and acetone. 3.87 g of a clear crystalline product are obtained which contains 93% of 6-deoxytetracycline, 17% of β-isomer and 8-10% of methacycline. Yield 58.5% for the α-isomer.

The present invention has the following advantages over the known method:

- it is more technologically feasible because it eliminates the use of ethanolic hydrogen chloride solution and the reaction mixture is treated with concentrated acidic solutions;

Ensure a more efficient separation of the mixture (Figures 1 and 2).

s. and does not include steps that would create favorable conditions for the formation of the 4-epimer.

Claims (1)

40 Process for the recovery of doxycycline hydrochloride of formula (I): Metacyclin derivatives of formula (II) wherein R is hydrogen or acyl. Hal represents halo45 from a reaction mixture obtained by catalytic hydrogenation, characterized in that the p-toluenesulfonic acid salt of doxycycline is separated by treatment with p-toluenesulphonic acid and recrystallized, followed by impurities before or after recrystallization. It is decomposed by alkaline treatment at pH 12, and the pure doxycycline p-toluenesulfonate in ethanol is converted to doxycycline hydrochloride with aqueous hydrochloric acid. 1 picture page Director of Economic and Legal Publishing - ') <· 84.5414.66-4 Alföldi Nyomda, Debrecen - · Responsible leader: István Benkő director ^r -