DE2433608C2 - Process for the preparation of 11a-chloro-5-oxytetracycline-6,12-hemiketal or its mineral acid salts - Google Patents

Description

The invention relates to an improved process for the preparation of I la-chloro-5-oxytetracycline-6,12-hemiketal or its mineral acid salts according to the preceding claims.

lla-chloro-S-öxyietracycline-e. ^ - hemiketal is a valuable intermediate for the production of commercially important antibiotics, namely e-demethyl-S-oxytelracycline and 6Ä-deoxy-5-oxytetracycline (US-PS 29 84 686 and 32 00 149). The US-PS 29 84 686 and 31 09 007 describe the preparation of the known compound by reacting 5-oxytetracycline with a chlorinating agent in an inert solvent at a temperature of about +25 to + 50 ⁰ C and a pH value close to the isoelectric Point of 5-Oxy'etracycline. The inert solvent is a water-miscible solvent. The product is precipitated by diluting the reaction mixture with water and isolated by filtration.

The BE-PS 7 77 356 describes the chlorination of S-oxytetracycline or the acid addition salts thereof in a suitable solvent at a temperature below 0 ⁰ C, while the pH is maintained between about 3.5 and 5, the I la- Chlor-5-oxyletracycline-6.12-hemiketalbase precipitates in the enol form. The hemiketal base is isolated and subsequently converted into the hydrochloride sulfosalicylate or p-toluenesulfonate salt by treatment with the corresponding acid at -10 to + 20T.

The known methods lead to non-reproducible and / or relatively poor yields of I la · ChloΓ · 5-oxytctracycline-6.l2-hcπliketalhydrochlorid or another acid addition salt, the quality of which is not always the same. causing difficulties result in the subsequent process steps in which the hemiketal product as an intermediate serves. In addition, the known methods require isolation of the hemiketal base prior to manufacture an acidic addition salt thereof.

In contrast, the invention permits seduction a simple isolation of I la-chloro-5-oxytciracyclin-6.l2-hemiketal in the form of a stable, crystalline S. hir addition salt by filtration or centrifugation. The product obtained in this way gives when it has been hydrated with hydrogen fluoride. essentially Quantitative healing of I la-chloro-ö-desmc-

thyt-ö-deoxy-ö-methylene-S-oxytetracycline. This is an important intermediate in the production of ö-desmethyl-e-deoxy-ö-methylene-S-oxytetracycline and 6a- deoxy-5-oxy tetracycline.

According to the method of the invention, 5-oxytetracycline reacted with a chlorinating agent in an inert solvent mixed with water Suitable chlorinating agents are chlorine, N-chloro-low alkanoic acid amides, such as N-chloroacetamide, hydrocarbon dicarboximides, such as N-chlorosuccinimide, N-chlorophthalimide, and N-chloro-N-lower alkanoylanilide, such as N-chloroacetanilide, N-chloropropionanilide, furthermore 3-chloro- and S.S-dichloro-S.S-dimethylhydantoin, Pyridinium perchloride hydrohalides, e.g. B. pyridinium perchloride hydrochloride and lower alkyl hypochlorites such as tert-butyl hypochlorite. It can be seen that im Generally commonly used chlorinating agents are suitable, but the above are given preferred. A particularly preferred chlorinating agent is N-chlorosuccinimide because of easy handling, the rapid implementation with 5-oxytetracycline and the resulting high yields of chlorinated product.

»Inert solvent is to be understood as meaning a solvent which is subject to the reaction conditions does not react in an undesirable manner with any starting compounds or end products. Very little experimental effort enables the choice of suitable solvents for the in the laboratory method according to the invention. The solvents are water-miscible solvents and are called Mixtures with water are used. Examples of such solvents are dioxane, tetrahydrofuran, acetone, Dimethyl ether of diethylene glycol. Dimethyl ether of ethylene glycol, acetonitrile, methyl ethyl ketone, monoethyl ether of ethylene glycol, N.N-dimethylformamide and N.N-dimethylacetamide. Such solvents can give a single phase reaction mixture for the chlorination reaction and a simple and complete Allow isolation of the desired hemiketal acid addition salt. A particularly suitable one Solvent is a mixture of acetone and water.

The chlorination is conducted at a temperature of - 10 to -40 performed ⁰ C and advantageously at a temperature from -30 to -40 ⁰ C. Higher temperatures, ie temperatures up to + 10 ° C. lead to side reactions which reduce the yield of the I la-chloro-6,12-hemikctalprodukt.

The 5-oxytetracycline can be used in the base form or as an acid addition salt is preferred because it is a stable, readily available form of the antibiotic.

A slight excess of the chlorinating agent, advantageously from 1.1 to 1.4 moles per mole S-oxytetracycline base or acid addition salt thereof, is generally used. The speed of implementation depends of course on the chosen Chlorinating agent from, but a complete reaction generally takes place in a few minutes.

The pH of the chlorination reaction mixture can range from 6.5 to 7.7 and should preferably be used in the range of 7.3 to 7.5 for best results. With regard to the difficulty From a practical point of view, it is easier to measure pH when using 5-oxytctracycline hydrochloride is used as a starting material, and the pH value is determined by a corresponding amount of iron Neutralization of the hydrochloride salt is required

is set. This makes 0.20-0.40 g of triethylamine per g of S-oxytetracycline hydrochloride (equivalent to I to 2 Moles of triethylamine per mole of oxyteiracycline hydrochloride or other addition salts of monobasic acids) used to achieve a suitable pH range.

Immediately after the chlorination reaction, which takes place at high speed, the reaction mixture is treated with a strong mineral acid in order to to lower the pH below 1.0. The mineral acid is, for. B. hydrochloric acid, sulfuric acid, hydrofluoric acid, Hydrobromic acid and perchloric acid used. The preferred mineral acid is hydrogen chloride either gaseous or in solution form, because this is the stable, easily isolable hydrochloride salt π forms, d. H. the 1 la-chloro-S-oxytetracycline-ö. ^ - hemiketal salt, which is generally used in the industrial production of eÄ-Deoxy-S-oxytetracycline will.

The Ua-Chlor-S-oxytetracycline-ö. ^ - hemiketal salt can be isolated from the mixture of seeds by adding a non-dissolving agent for the salt. the Insolubility of the hydrochloride salt in acetone is the main reason why acetone-water is preferred Solvent in this process is, and the reason why hydrogen chloride is used as an acidifying agent in the the last stage of the process is preferred.

The choice of the best reaction conditions, e.g. B. the temperature, the solvent, the chlorinating agent, the acidification agent and the method of isolation can be taken after routine experimentation will.

example 1

lla-chloro-S-oxytetracyclii 6,12 hemiketal hydrochloride

A jacketed and glass-lined reaction vessel charged with acetone (24 L), deionized water (4.5 L) and S-oxytetracycline hydrochloride (5 kg! 0.06 mol) is stirred and filled with liquid nitrogen cooled 40 ⁰ C - on. Precooled to -40 ° C triethanolamine (161, 11.5 mol) is to keep within 30 seconds while simultaneously introducing liquid nitrogen to the temperature at -40 ⁰ C, the mixture was added. A slurry of N-chloro-succinimide (1695 kg, 11.5 mol) in acetone (3.8 I) is then to keep within 2 minutes with simultaneous and continual introducing liquid nitrogen to the temperature at -40 ⁰ C. , admitted. When the addition is complete, the introduction of liquid nitrogen is stopped and the reaction mixture is stirred for 3 minutes. A solution of acetone (54 l), pre-cooled to 8 ° C., the hydrogen chloride gas 1.2 kg) was added. A slurry of N-chlorosuccin was added over a period of 2 minutes. To promote the precipitation of the hydrochloride salt, 125 g of crystalline 11 a-chloro-S-oxytetracycline>, 12-hemiacial hydrochloride are added to the reaction mixture when about half of the acetone-HCl solution has been added. Crystallization begins immediately. The reaction mixture is heated to 15-18 ° C using water having a temperature of 60 ° C in the jacket. The product is granulated for one hour at 15 ° to 20 ° C and then for 1.5 hours at -5 ° to -10 ° C. The product is isolated by filtration, washed with acetone (3 χ 3 l) and dried at 30.degree. To 35.degree. C. in a vacuum dryer. Yield 78.4 °, above sea level

Similar results are obtained when the chlorination is carried out at temperatures of -30.degree. C., -20.degree. ^{C. and -10.degree.}

Example 2

The procedure of Example 1 is repeated, however using the following acids in acetone solution instead of hydrogen chloride:

Hydrogen bromide
Hydrogen fluoride
sulfuric acid
Perchloric acid
concentrated hydrochloric acid

In any case, the acid addition salts will precipitate promoted by adding seed crystals of the corresponding acid addition salts.

Example 3

The procedure of Example 1 is repeated, but using 5-oxytetracycline in the following Forms as starting material:

(a) free base

(b) hydrofluoride

(c) Hydroiodide

(d) perchlorate

(e) naphthalene sulfonate

(f) sulfosalicylate

(g) p-toluenesulfonate
(h) citrate

(i) Tartrate 50 (j) Benzoate In each case, the yields are Ila-chloro-5-oxytet / acycline-ö. ^ - hemiketal hydrochloride comparable to the yields obtained according to example 1.

Claims (2)

Patent claims: J. Process for the preparation of Ua-chloro-5-oxytetracycline-6,12-hemiketal or its mineral acid salts by chlorinating 5-oxytetracycline or one of its addition salts with a chlorinating agent such as N-chlorosuccinimide in an inert solvent mixed with water at lower Temperature and subsequent addition of a mineral acid, characterized in that the chlorination is carried out at a temperature of -10 to -40 ⁰ C and a pH of 64 to 7.7 and then a pH of less than 1 with the strong mineral acid , 0 is set. 2. The method according to claim 1, characterized in that that the chlorination is carried out at a temperature of -30 to -40 ° C.