DD219021A3 - PROCESS FOR PREPARING 11A-CHLORO-5-HYDROXY-TETRACYCLINE-6,12-HEMICETAL - Google Patents

Abstract

The invention relates to a process for preparing the 11a-chloro-5-hydroxytetracycline-6,12-hemiketal by chlorinating 5-hydroxytetracycline. The aim of the invention is a process in technologically simple to carry out procedure and using a cost effective chlorinating agent as N-chlorosuccinimide. It has been found that the alkali salts of N-monochloro-arylsufonamides are excellent chlorinating agents for chlorinating the 5-hydroxy-tetracycline at the 11a position to form the 6,12-hemiketal in the enol form.

Description

Process for the preparation of 11a-chloro-5-hydroxy-tetracycline-6,12-hemiketal Field of application of the invention

The invention relates to a process for preparing the 11a-chloro-5-hydroxytetracycline-6,12-hemiketal by chlorinating 5-hydroxytetracycline. The thus obtained 11 a-chloro-S-hydroxy-tetracycline-ej2-hemiketal can be converted in a known manner to 6-methylene-e-dimethyl-e-deoxy-S-hydroxy-teträcyclin, a valuable antibiotic.

Characteristic of the known technical solutions,

For the preparation of the Ha-chloro-S-hydroxy-tetracycline e ^ -hemiketals several methods have already been proposed (USP 2984686, DE-OS 2164840, DD-AP 113527). In all of the proposed methods, 5-hydroxy-tetracycline is chlorinated in a reaction-inert, water-miscible solvent, with the following chlorinating agents being useful: chlorine, N-chloroalkanoic acid amides, chlorodicarboximides, N-lower alkanoylanilides, chlorodimethylhydantoin, pyridinealchloride hydrochloride, and lower alkyl hypochlorites. According to the process of USP 2984686, chlorination of 5-hydroxytetracycline as a base at temperatures of 0 to 50 ⁰ C, only relatively low yields (~ 40% of theory) - were obtained because a part of the.Chlorierungsproduktes in the less stable Ketoform accumulates. In the process of DE-OS 2164840 obtained by buffering the reaction mixture with triethylamine to a pH of 3 to 5, preferably 4 to 4.5 at the chlorination carried out between -15 and -4 ⁰ C better yields by spontaneous crystallization of the stable enol form. The method of DD-AP 113527 chlorinated, however, at even lower temperature (-40 ⁰ C) and stronger buffering of the reaction mixture with triethylamine to pH = 6.5 to 7.7, especially 7.3 to 7.5 and precipitates the reaction product the reaction mixture as salt of the enol form with mineral acid in ~ 78% d. Th. Yield.

Common to all previous methods, apart from the use of water-miscible solvents, is the use of N-chlorosuccinimide as the chlorinating agent, which is preferred in the claims and exclusively described in the examples, although this substance is by far not the most cost-effective of all the chlorinating agents indicated as useful.

Although the other mentioned in the known process proposals chlorinating agent can be used instead of N-chlorosuceinimide for 'chlorination, but in principle give lower yields than N-chlorosuccinimide. N-chloro- and N, N-dichloro-arylsulphonic acid amides have also been used for special chlorinations (see Houben Weyl, Methods of Organic Chemistry, Georg Thieme Verlag Stuttgart, 4th Edition BdV / 3 p.808 ff., And BdIX S .645).

These compounds apparently not yet used for the chlorination of 5-hydroxy-tetracycline can be used as well as N-chlorosuccinimide, but offer no advantages over this.

In addition, both of the two methods of DE-OS 2164840 and DD-AP 113527, which proceed satisfactorily, require precise adherence to a narrow pH range, which is obviously dependent on the process. However, experience has shown that the measurement of pH values in solutions which are not or only slightly aqueous, even at temperatures below ^-5.degree. C., presents considerable difficulties in practice.

ZFeI the invention

The aim of the present invention is a process for the preparation of 1-chloro-S-hydroxy-tetracycline-e, 2-hemiketal in a technologically simple manner and using a less expensive chlorinating agent as N-chlorosuccinimide. The product should be obtained in at least the same yield as according to the best of the known processes in the form of the enol.

Presentation of the essence of the invention>

The object then was to find a new, more cost-effective chlorinating agent which, without the difficulty of adjusting a pH range, would be capable of chlorinating the 5-hydroxytetracycline in high yield to give the desired 11a-chloro-5-hydroxytetracycline-6,12- hemiketal allowed.

The object has now surprisingly been achieved by finding that the alkali salts of N-monochloro-arylsulfonamides are excellent chlorinating agents for chlorinating the 5-hydroxy-tetracycline at the 11a position to form the 6,12-hemiketal in the enol form, Although these compounds have been used in addition to their commercial use as a disinfectant, although as an oxidizing agent but not as a chlorinating agent.

(Houben-Weyl, Methods of Organic Chemistry Bd IX p. 644) It was also surprising that the desired chlorination product was formed in high quality and excellent yield, without one of the previously recognized as optimal pH ranges (4 to 4.5 or 7.3, to 7.5) before or during the reaction.

For example, when using N-chlorosulfonamide alkali metal salts under the conditions mentioned in DD-AP 113527, the 11a-chloro-6,12-hemiketal is only obtained in yields of 60% with considerable amounts of undesired ketoform.

In the inventively recognized as optimal conditions 5% more yield over the DD-AP 113527 are achieved.

This smooth reaction was also unexpected because the strongly polar salts are sparingly soluble at the temperatures used in only slightly hydrous organic solutions.

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A particularly favorable representative of the class of compounds mentioned is N-chloro-p-toluenesulfonamide sodium (trade name Chloramin T). The reaction proceeds under very tired conditions in a very short reaction time only slightly exothermic and almost quantitative to a solution of the 11a-chloro-5-hydrosxytetracyclin-6,12-hemiketals. The advantage of using the N-chloro-arylsulfonsäureamidsalze in this reaction was expressed in the fact that only a single cooling of the solution or suspension of 5-hydroxytetracycline in, for example, aqueous acetone to -10 ...-40 ⁰ C is required and at the addition of the chlorinating agent did not have to be cooled further. The temperature then rose to -15 .. + 5 ⁰ C at. The results of the pH measurement in the reaction mixture were interesting. Using the amount of N-monochloro-p-toluenesulfonamide sodium required to give good yields, from 1.1 to 1.3 moles per mole of 5-hydroxytetracyclin gave a pH of 5.1 to 6.3. With the preferred amount of chlorinating agent of 1.2 mol, a pH of 5.8, a value which does not lead to the goal in the known methods.

It was surprising that good yields and product qualities were achieved, although in the process according to the invention adjusting pH (5.1 to 6.3) does not lie in any of the pH ranges previously found to be optimal (pH = 3 to 5 in DE-OS 2164840 and pH = 6.5 to 7.7 in DD-AP 113527).

A decisive advance over the state of the art also exists in this! that no measurement of the pH value is necessary. The pH measurement at temperatures below -10 ⁰ C represents an unsatisfactory solved measurement problem. The isolation of the product can be carried out in the usual manner, for. B. by precipitation with hydrochloric acid as the hydrochloride, which does not have to be worked anhydrous. In this case, part of the sodium originating from the chloramine T precipitates out as sodium chloride and decisively improves the filterability of the product. In further processing, for. B. by the known dehydration with hydrogen fluoride to Ha-chloro-metacyclin does not interfere with the sodium chloride, there are yields of Ha-chloro-metacyclin of> 95% d., Th. receive. ·

The following examples are intended to illustrate the invention. '

Exemplary embodiments Example 1

6,25kg (12.5 mol) of S-hydroxytetracycline hydrochloride are dissolved in a mixture of water and 5.51 acetone 3Ol or suspended and the mixture cooled to-30 to ⁰ C -4o. 4.25kg (15 moles) of chloramine T are added quickly (in 1 to 2 minutes), leaving 5 to 6 minutes. stirred. Increasing the temperature to -15 ... -10 ⁰ C produces an almost clear yellow solution. By adding a mixture of 87.51 acetone and 2.251 conc. Hydrochloric acid, precooled to 0 to +5 ⁰ C, the reaction product is precipitated. The mixture is stirred for 1 hour at 18 to 20 ⁰ C and 1.5 hours at -5 to -1O ⁰ C after, filtered, washed with acetone and dried.

There are obtained 6.9 kg of 1-chloro-3-hydroxytetracycline-e 1 -hemiketal hydrochloride dihydrate having a NaCl content of about 14% corresponding to 5.93 kg of pure product (83% of theory). F: 212 to 216 (Z), [af ° -22.5 ° (c = 1, methanol with 1% HCl) based on NaCl and anhydrous substance. The product has no IR band above 1666 cm ^-1 , indicating the absence of the unwanted ketoform.

Example 2

In order to show the influence of different amounts of the chlorinating agent, Example 1 is repeated with different amounts of chloramine T. You get the following results:

Mole chloramine T / mole OTC yield hemiketal -

1 40%

1.4. 70%.

1.6. 54% -

Example 3

Example 1 is repeated, but instead of oxytetracycline hydrochloride, oxytetracycline dihydrate is used together with the stoichiometric amount of hydrochloric acid. There are 63.6% d. Th. Obtained on Ha-chloro-oxytetracycline hemiketal.

Claims (4)

1. A process for the preparation of Ha-chloro-B-hydroxytetracycline 6,12-hemiketal by chlorinating oxytetracycline in a water-miscible solution with + - 'at temperatures between -40 ⁰ C to +5 ⁰ C and isolation of the reaction product by precipitation with hydrochloric acid, dadi ι characterized in that a alkali metal salt of an N-Monochlorarylsulfonamids is used as the chlorinating agent. -1-242 736 5 Invention claims: 2. The method according to item 1, characterized in that the N-Monocnlorarylsulfoamid-alkali metal salt is used in an amount of 1 to 1.6 moles, preferably 1.2 to 1.3 moles per mole of oxytetracycline. 3. The method according to item 1, characterized in that the N-monochloroarylsulfonamide-alkali salt, the N-monochloro-p-toluenesulfonamide sodium is used. 4. The method according to item 1, characterized in that the reaction at a pH of 5 to 6.5, preferably 5.5 to 6 is performed.