JPS5835982B2 - 5- Oxytetracycline 11A- Ensocahouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a strong mineral acid addition salt of 11a-chloro-5-oxytetracycline-6,12-hemiketal.

11a-chloro-5-oxytetracycline 6,12
- Hemiketals are commercially important antibiotics 6-dimethyl-5-oxytetracycline and 6α-deoxy-5-oxytetracycline (U.S. Pat. No. 29,846).
86 and 3200149).

U.S. Patents 2984686 and 3109007 (each with 1
5 on May 16, 1963 and October 29, 963).
- Reacts oxytetracycline with an inert solvent width of approx. -25
It is mentioned that the hemiketal is prepared by reaction with a chlorinating agent at a temperature between 50°C and 50°C and a pH near the isoelectric point of 5-oxytetracycline.

The reaction inert solvent is a water-miscible solvent.

The product is precipitated by diluting the reaction mixture with water and passing through the mouth.

Belgian patent 777 granted on April 17, 1972
356, 11a-chloro-5-
It is stated that oxytetracycline-6,12-hemiketal base spontaneously precipitates as the enol form.

Isolate the hemiketal base above and subsequently
It is converted to the hydrochloride, sulfosalicylate or p-)luenesulfonate by treatment with a suitable acid at 0°C.

In the prior art, only unsatisfactory or relatively low yields of 11a-chloro-5-oxytetracycline-6,12-hemiketal hydrochloride or other acid addition salts are obtained, and the quality is not always satisfactory. Instead, this creates difficulties in each subsequent step in which the hemiketal product is to serve as an intermediate.

Additionally, the prior art requires isolation of the hemiketal base prior to the preparation of the acid addition salt.

However, 5-oxytetracycline is
By a method consisting of chlorination in a reaction inert solvent at a temperature of 0 °C and a pH of 6.5 to 7.7, immediately followed by reducing the pH of the reaction mixture to a value below 1.0 by the addition of a strong mineral acid. 11a-chlor-5 of satisfactory and excellent quality
It has been found that -oxytetracycline-6,12-hemiketal hydrochloride and other strong mineral acid addition salts can generally be prepared in high yields.

11a-chloro-5-oxytetracycline-6.1
The 2-hemiketal is recovered as a strong mineral acid addition salt.

According to this invention, 5-oxytetracycline or an acid addition salt thereof is treated with a chlorinating agent in a reaction inert solvent.
A-chlorination to produce 11a-chloro-5-oxytetracycline-6,12-hemiketal is provided, wherein the chlorination is carried out between -10°C and -
The water-miscible reaction is carried out in an inert solvent at a temperature of 40 DEG C. and a pH of 6.5 to 7.7, followed by lowering the pH of the reaction mixture below 1.0 by addition of a strong mineral acid.

In this method, 11a-chloro-5-oxytetracycline=6,12-hemiketal can be easily recovered as a stable crystalline strong mineral acid addition salt by oral filtration or centrifugation.

Dehydration of the product thus obtained with hydrogen fluoride always yields essentially equal yields of 11a-chloro-6-
Provides demethyl-6-buoxy-6-methylene-5-oxytetracycline.

This compound is an important intermediate in the synthesis of 6-demethyl-6-buoxy-6-methylene-5-oxytetracycline and 6α-deoxy-5-oxytetracycline.

The process of this invention consists of reacting 5-oxytetracycline with a chlorinating agent in a reactive inert solvent.

Suitable chlorinating agents include chlorine, N-chloro lower alkanoamides such as N-chloroacetamide, hydrocarbon dicarboxylic imides such as N-chlorosuccinimide,
phthalimide and N-lower alkanoylanilide,
For example, N-chloroacetanilide, propionanilide: 3-chlor and 3,5-dichlor, 5,5-dimethylhydantoin, pyridinium perchloride hydrohalides, such as pyridinium perchloride hydrochloride, and lower alkyl hypochlorites, such as It is t-butyl chlorite.

Generally, any chlorinating agent commonly used in the art can be used in the reaction, but those mentioned above are preferred.

A preferred chlorinating agent is N-dichlorbacimide.

This is because this chlorinating agent is easy to handle and use;
Reaction with 5-oxytetracycline is fast and gives high yields of chlorinated products.

"Reaction-inert solvent" refers to a solvent that does not react undesirably with either the starting compound or the final product under the conditions of the reaction.

A minimum of experimental experience will be sufficient to select an appropriate solvent for this method.

Preferred solvents are water-miscible solvents and their mixtures with water.

Examples of such solvents are dioxane, tetrahydrofuran, acetone, dimethyl ether of diethylene glycol (Sifrim), dimethyl ether of ethylene glycol (Monoglyme), acetonitrile, methyl ethyl ketone, monoethyl ether of ethylene glycol, N-N-
dimethylformamide, N-N-dimethylacetamide, and mixtures of such solvents with water.

Such solvents provide a single-phase reaction mixture for the chlorination reaction and facilitate and complete recovery of the desired hemiketal acid addition salt.

A particularly useful solvent is a mixture of acetone and water.

Chlorination is carried out at a temperature of -10°C to -40°C, preferably -30°C.
It is carried out at a temperature of between -40°C and -40°C.

Higher temperatures, ie up to +10°C, can be used but are generally avoided to minimize side reactions which tend to reduce the yield of 11a-chloro-6,12-hemiketal product.

Lower temperatures can also be used, but are avoided to eliminate the need for special cooling means.

5-oxytetracycline can be used in base form or as an acid addition salt.

Hydrochloride is the preferred salt because it is a stable and readily available form of the antibiotic.

A slight excess of chlorinating agent, preferably from 1.1 to 1.0% per mole of 5-oxytetracycline/base or acid addition salt thereof.
4 moles are commonly used.

The reaction rate depends of course on the chlorinating agent selected, but is generally complete in minutes.

The pH 1 when operating in anhydrous solvents, i.e. the apparent pH of the chlorination reaction mixture, can range from 6.5 to 7.7, but for optimal yields it should be between 7.3 and 7.7.
You must throw within the range of 5.

Since it is difficult to measure the apparent pH,
When using 5-oxytetracycline hydrochloride as a reactant, it is more convenient, at least from a practical standpoint, to define this parameter in terms of the amount of base used to neutralize the hydrochloride.

Based on this, 0.20 to 0.4 (l) of triethylamine per 11 of 5-oxytetracycline hydrochloride (equivalent to 1 to 2 moles of triethylamine per mole of oxytetracycline hydrochloride or other monobasic acid addition salt) )
to the appropriate pH range.

Immediately after the rapidly occurring chlorination reaction, the reaction mixture is treated with a strong mineral acid to reduce the pH to below 1.0.

Mineral acids such as hydrochloric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid, and perchloric acid can be used.

A preferred mineral acid is the stable and easily recoverable hydrochloride salt of 11a-chloro-5-oxytetracycline-6,12-hemiketal which is commonly used in the industrial production of 6α-deoxy-5-oxytetracycline. Because it forms a salt, it is hydrogen chloride in gaseous or solution form.

11a-chloro-5-oxytetracycline-6.1
The 2-hemiketal salt can be recovered from the acid mixture by addition of a non-solvent for the salt.

The insolubility of the hydrochloride salt in acetone is the primary reason why acetone-water is the preferred solvent for this process and why hydrogen chloride is the preferred acidifying agent for the final step of this process.

Selection of the best reaction conditions, temperature, solvent, chlorinating agent, acidifying agent and recovery method is a matter of routine experimentation.

Example 1 11a-chloro-5-oxytetracycline 6,12
- Hemiketal hydrochloride acetone (24 liters), deionized water (4.5 liters) and 5-oxytetracycline hydrochloride (5 kg
, 10.06 mol) was stirred in a boxwood-lined reaction vessel, and the mixture was heated to 14 mol with liquid nitrogen.
Cooled to 0°C.

Triethylamine (1,617 ttr, 11.5 mol), previously cooled to -40°C, was added to the mixture for 30 seconds while simultaneously adding liquid nitrogen to maintain the temperature at -40°C.

Acetone (3,8
! J Tuttle) Medium N chlorosuccinimide (1,695k
11.5 mol) of the slurry was simultaneously and continuously added with liquid nitrogen to maintain the temperature at -40° C. for 2 minutes.

When the addition was complete, the introduction of liquid nitrogen was stopped and the reaction mixture was stirred for 3 minutes.

A solution of acetone (54 liters) to which hydrogen chloride gas (9.33 mol in 1,2) had been added and precooled to 8° C. was introduced into the reaction mixture over a period of 2 minutes.

The crystalline 11a chloro-
5-oxytetracycline-6,12-hemiketal hydrochloride was added to the reaction mixture.

Crystallization began immediately.

The reaction mixture was diluted with 60°C water in the jacket.
Warmed to is°C.

The product was heated for 1 hour at 15°-20°C and then at -5° to -1
Granulation was carried out for 1.5 hours at 0°C.

The product was collected by filtration, washed with acetone (3 x 3 liters) and dried in a vacuum oven at 300-35°C (74.8% yield).

Similar results were obtained when chlorination was carried out at temperatures of -30°, -20° and -10°C.

Example 2 The procedure of Example 1 was repeated, except that instead of hydrogen chloride, an equal volume of the following acid in acetone was used.

Hydrogen bromide, hydrogen fluoride, sulfuric acid, perchloric acid, concentrated hydrochloric acid In each case, precipitation of the acid addition salt is facilitated by the addition of seeds of the corresponding acid addition salt.

Example 3 The procedure of Example 1 was repeated except that equal amounts of 5-oxytetracycline of the following form were used as starting materials: (a) free base, (b) hydrofluoric acid salt, (c)
iorate, (d) perchlorate, (e) naphthalene sulfonate, (f) sulfosalicylate, (g) p
- toluenesulfonate, (h) citrate, (i
) Tartrate Salt, (j) Stable Fragrance Salt In each of the above cases, yields of 11a-chloro-5-oxytetracycline 6 12-hemiketal hydrochloride were obtained corresponding to Example 1.

Claims (1)

[Claims] 15-oxytetracycline or its acid addition salt at a temperature of -10°C to -40°C and a pH of 6.5 to 7.
．． lla-chlorination with a chlorinating agent in a water-miscible reaction inert solvent to form the lla-chloro-5-oxytetracycline-6,12-hemiketal in step 7, followed by adjusting the pH of the reaction mixture. lla, characterized in that a strong mineral acid is added until the lla becomes less than 1.0.
A method for producing a strong mineral acid addition salt of chloro-5-oxytetracycline-6,12 hemiketal.