IL45119A - Process for the 11a-chlorination of oxytetracycline - Google Patents

Description

froeeee for the lla-ohlorination of oxytetracycline PPIZEfi UfO.

P.O. (Ph) This invention relates to an improved process for the preparation of lla-chloro-5-oxytetracycline-6,12-hemiketal by the chlorination of 5-oxytetracycline, and the recovery of lla-ehloro-5-0xytetracycline-6,12-hemiketal as an acid addition salt at a pH less than 1.0. lla-Chloro-5-ox tetracyeline-6 , 12-hemiketal is a valuable intermediate for production of the commercially important antibiotics 6-demethyl-5-Qxytetracycline and 6^ deoxy-5- xytetracycline (United States Patents 2,984,686 and 3,200,149). United States Patents 2,984,686 and 3,109,007 issued May 16, 1961 and October 29, 1963, respectively, describe its preparation by the reaction of 5-oxytetracycline with a chlorinating agent in a reaction-inert solvent at a temperature of from about -25°C. to +50°C, and a pH valine near the isoelectric point of the 5-oxytetracycline. The reaction inert solvent is a water-miscible solvent. The product is precipitated by dilution of the reaction mixture with water and filtration.

Belgian Patent 777,356, granted April 17, 1972, describes the chlorination of 5-oxytetracycline or its acid addition salts in a suitable solvent at a temperature below 0°C. while maintaining the pH between about 3.5 and 5, to spontaneously precipitate lla-chloro-5-oxytetracycline-6,12-hemiketal base in the enolic form. The hemiketal base is isolated and subsequently converted to the hydrochloride, sulfosalicylate or p-toluenesulfonate salt? by treatment wi the appropriate acid at -10°C. to +20°C.

The prior art processes afford inconsistent and/or relatively poor yields o lla-chloro-5-oxytetracycllne-6,12-hemiketal hydrochloride or other acid addition salt, the quality of which is not always consistent thus giving rise to difficulties in subsequent process steps for which the hemiketal product serves as intermediate* Additionally, they require isolation of the hemiketal base prior to preparation of an acid addition salt thereof.

It has now been found that lla-chloro-5-oxytetra^ cycline-6,12-hemiketal hydrochloride and other acid addition salts of consistent and excellent quality can be generally prepared in high yield by a process which comprises chlorina <-ing 5-*oxytetracycline at a temperature of from -10°C. to -40°C. and pH from 6.5 to 7.7 in a reaction-inert solvent followed by immediate lowering of the pH of the reaction mixture to less than 1.0 by addition of a strong mineral acid. The lla-chloro-5-oxytetracycline-6 ,12-hemiketal is recovered as an acid addition salt.

According to the invention there is provided a process for the lla-chlorination of 5-oxytetracycllne or an acid addition salt thereof by means of a chlorinating agent in a reaction inert solvent to provide lla-chloro-5- xytetra-cycline-6 , 12-hemiketal , wherein the chlorination is conducted at a temperature of from -10°C. to -40°C. and a pH of from 6.5 to 7· 7 in a water-miscible reaction-inert solvent, followed by addition of a strong mineral acid to lower the pH of the reaction mixture thus obtained to less than 1.0.

The process normally permits easy recovery of lla-chloro-5-oxytetracycline-6,12-hemiketal as a stable, ■ crystalline acid addition salt by filtration or centrifuga-r tion. The product thus obtained, when dehydrated with hydrogen fluoride, affords essentially /^quantitative yields of lla-chloro-6-demethyl-6-deoxy-6-methylene-5-oxytetracycline . This latter compound is an important intermediate in the synthesis of 6-demethyl-6-deoxy-6-raethylene-5-oxytetracycline and of 6« -deoxy-5-oxytetracycline .

The process of this invention comprises reacting 5-oxytetracycline with a chlorinating agent in a reaction-inert solvent. Suitable chlorinating agents are ohlorine, N-chloro lower alkanoic acid amides, e.g., N-chloroacetamlde, hydrocarbon dicarboxylic acid imides, e.g., N-chlorosuccin-imide, phthalimide and N-lower-alkanoylanilides , e.g., N-chloroacetanilide, propionanilide ; 3-chloro and 3,5-di-chloro, 5»5-dimethylhydantoin, pyridinium perchloride hydro-halides, e .g. , pyridinium perchloride hydrochloride, and lower alkyl hypochlorites, e.g., tertiary butylhypochlorite . It is obvious that, in general, chlorinating agents commonly employed in the art are operable, but the above are favored. The preferred chlorinating agent is N-chlorosuccinimide because of its ease of handling and use, its rapid reaction with 5-oxytetracycline, and the high yields of chlorinated product it affords.

By "reaction-inert solvents" is meant a solvent which, under the conditions of the reaction, does' not react in an undesired manner with either starting compounds or final products. A minimum of laboratory experimentation will permit the selection of suitable solvents for the present process. The favored solvents are water-miscible solvents and mixtures thereof with water. Exemplary of such solverf¾ are dioxane, tetrahydrofuran, acetone, dimethyl ether of di-ethylene glycol (diglyme), dimethyl ether of ethylene glycol (monoglyme), acetonitrile , methyl ethyl ketone, monoethyl ether of ethylene-glycol, N,N-dimethylformamide, N,N-dimethyl*-acetamide, and mixtures of such solvents with water. Such solvents can provide a single phase reaction mixture for the chlorination reaction and permit easy and complete recovery of the desired hemiketal acid addition salt. An especially useful solvent is a mixture of acetone and water.

The chlorination is conducted at a temperature of from -10°C. to -40°C. and desirably at a temperature of from -30°C. to -40°C. Higher temperatures, that is, temperatures up to +10°C, can be used but are generally avoided in order to minimize side-reactions which tend to reduce the yield of the lla-chloro-6,12-hemiketal product. Lower temperatures can also be used but are avoided in order to eliminate the need for special cooling means.

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

A slight excess of chlorinating agent, desirably from 1.1 to 1.4 moles per mole of 5-oxytetracycline base or acid addition salt thereof is generally used. The rate of reaction does, of course, depend upon the chlorinating agent selected, but is generally completed in a matter of minutes.

The pH, more appropriately when operating in an anhydrous solvent, the apparent pH, of the chlorination re-action mixture can range from 6.5 to 7.7 and, advantageously, should be in the range of 7·3 to 7.5 for optimum yield. ^ In view of the difficulty in measuring apparent pH it is more convenient, at least from a practical standpoint when using 5-oxytetracycline hydrochloride as reactant, to define this parameter in terms of the amount of base used to neutralize the hydrochloride salt. On this basis, from 0.20 to 0.40 gram of triethylamine per gram of 5-oxytetracycline hydrochloride (equivalent to from one to two moles of triethylamine per mole of oxytetracycline hydrochloride, or other monobasic acid addition salt) are used to achieve the appropriate pH range.

Immediately following the chlorination reaction, which occurs at a rapid rate, the reaction mixture is treated with a strong mineral acid to drop the pH to below 1,0.

Mineral acids such as hydrochloric, sulfuric, hydrofluoric, hydrobromic , perchloric, can be used. The preferred mineral acid is hydrogen chloride, either in gaseous or solution form, since it forms the stable, easily recoverable hydrochloride salt, the salt of lla-chloro-5-oxytetracycline-6,12-hemiketal generally used in the industrial production of 6 < -deoxy-5- xytetracycline.

The lla-chloro-5-oxytetracycline-6,12-hemiketal salt can be recovered from the acid mixture by addition of a non^solvent for the salt. The insolubility of the hydro-chloride salt in acetone is the main reason why acetone-water is the favored solvent for this process and the reason for hydrogen chloride being the preferred acidifying agent for the final step of this process.

The selection of the best reaction conditions, e.g., temperature, solvent, chlorinating agent, acidifying agent and recovery method, Is a matter of routine experimentat on EXAMPLE I lla-Chloro-5-Oxytetraeycline- , 2-Hemiketal Hydrochloride A Jacketed, glass-lined reactor charged with acetone (24 liters), deionized water (4.5 liters) and 5-oxytetra-cycline hydrochloride (5 kg., 10.06 moles) is stirred and cooled to -40°C. by means of liquid nitrogen. Triethylamine (1.6 liters, 11.5 moles), pre-cooled to -40°C. is added to the mixture over a 30-second period with simultaneous addi-tion of liquid nitrogen to maintain the temperature at -40°C. A slurry of N-chlorosuccinimide (1.695 kg., 11.5 moles) in acetone (3-8 liters), pre-cooled to -40°C, is then added over a two-minute period with simultaneous and continuous addition of liquid nitrogen to hold the temperature at -40°C. When the addition is complete, the introduction of liquid nitrogen is stopped and the reaction mixture stirred for three minutes. A solution of acetone (54 liters), pre-cooled to 8°C. , to which hydrogen chloride gas (1.2 kg., 33 moles) has been added is then introduced into the reac-tion mixture over a two-minute period. To expedite precipitation of the hydrochloride salt 125 g. of crystalline 11a-chloro-5-oxytetracycline-6,12-hemiketal hydrochloride are added to the reaction mixture when approximately half of the acetone HC1 solution is added. Crystallization begins immediately. The reaction mixture is warmed to 15°-l8°C.

Using 60°C. water in the jacket. The product is granulated for one hour at 15°-20°C. and then -5° to -10°C. for 1.5 hours. The product is recovered by filtration, washed with acetone (3 3 liters) and dried at 30°-35°C. in a vacuum dryer (yield = 78. ¾).

Similar results are obtained when the chlorination is conducted at temperatures of -30°, -20° and -10°C» EXAMPLE II The procedure of Example I is repeated, but using, in place of hydrogen chloride, equivalent amounts of the following acids in acetone solution: hydrogen bromide hydrogen fluoride sulfuric acid perchloric acid concentrated hydrochloric acid In each instance, precipitation of the acid addition salts is expedited by addition of seed crystals of the corresponding acid addition salt.

EXAMPLE III The procedure of Example I, is repeated, bu using as starting material, an equivalent amount of the following forms of 5-oxytetracycline : (a) free base, (b) hydrofluoride salt, (c) hydroiodide salt, (d) perchlorate salt, (e) naphthalene sulfonate salt, (f) sulfosalicylate salt, (g) p^-toluenesulfonate salt , (h) citrate salt , (i) tartrate salt, (J) benzoate salt, In each instance yields of lla-chloro-5-oxytetra-cycline-6,12-hemiketal hydrochloride comparable to those of

Claims (9)

P.C. (Ph) 55124

1. A process for the lla-chlorination of 5-oxytetra-cycline or an acid addition salt thereof by means of a chlorinating agent in a reaction inert solvent to provide 11a-chloro-5-oxytetracycline-6,12-hemiketal, in which the chlor-ination is conducted at a temperature of from -10°C. to -40°C. and a pH of from 6.5 to 7· 7 in a water-miscible reaction-inert solvent, followed by addition of a strong mineral acid to lower the pH of the reaction mixture thus obtained to less than 1.0.

2. A process according to claim 1, wherein the 11a-chloro-5-oxytetracycline-6,12-hemiketal is recovered as a mineral acid addition salt.

3. A process according to either of claims 1 or 2, wherein the chlorinating agent is N-chlorosuccinimide .

4. A process according to any one of claims 1, 2 or 3, wherein the strong mineral acid is hydrogen chloride.

5. A process according to any one of the preceding claims, wherein the reaction inert solvent is aqueous acetone.

6. A process according to any one of the preceding claims, wherein the chlorination is conducted at a temperature of from -30°C. to -40°C.

7. A process according to any one of the preceding claims, wherein 5-oxytetracycline is used as the hydrochloride salt.

8. A process for the lla-chlorination of 5-oxytetra- cycline or an acid addition salt as claimed in Claim 1 substantially as described in the Examples.

9. lla-Chlorinated-5-oxytetracycline-6,12-hemiketal or its acid addition salt whenever prepared by the process as claimed in Claim 1 substantially as described.