HU199389B - Process for producing chloro-oxytetracycline-hemiketal-hydrobromide salt - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a solvate of the novel chloro-5-oxy-tetracycline-6,12-hemiketal hydrobromide, a hydrate thereof and / or an organic solvent thereof and, if desired, an α-chloro-6-deoxy-6-demethyl-6. for the production of methylene-5-oxytetracycline and its salts, by the formation of a hydrohalide salt of 5-oxytetracycline with aqueous hydrochloric acid or preferably hydrogen bromide in acetone, preferably hydrobromide, which is chlorinated without isolation. treating tetracycline-6,12-hemiketate with concentrated aqueous hydrobromide isolates the hydrate of the crystalline hydrobromide salt and / or solvate of the organic solvent and dehydrates, if desired, with 1 to 2 moles of dehydrating compound. EN 199389 Scope of the message: 8 pages, 4 formulas -1-

Description

The present invention relates to a process for preparing la-chloro-5-oxytetracycline-6,12-hemiketal hydrobromide (III), a hydrate thereof and / or a solvate of an organic solvent and, if desired, a la-chloro-6- (IV) salt thereof. for the preparation of deoxy-6-demethyl-6-methylene-6-oxytetracycline and its salts from the 5-oxytetracycline or its hydrate of formula I by formation of an acid addition salt in the presence of a water and water miscible organic solvent at pH 6-8, benzenesulfone chloramide by chlorination with sodium (neomagnol) or N-chlorosuccinimide followed by reaction of the resultant lla-chloro-5-oxytetracycline-6,12-hemiketal (II) or its hydrate with hydrogen halide, and optionally by dehydrating with a dehydrating mixture of chlorosulfonic acid and formic acid such that a hydrohalide salt of 5-oxytetracycline or hydrate of formula (I) with aqueous hydrochloric acid or hydrobromic acid in acetone is preferred. to form a hydrobromide which is chlorinated without isolation, in the presence of methanol for the hydrobromide, and treated with concentrated aqueous hydrobromic acid, 11a-chloro-5-oxytetracycline-6,12-hemiketal (II), preferably without isolation from the reaction mixture. (-20) - (+ 60) ° C and the crystalline precipitated lla-chloro-5-oxytetracycline-6,12-hemiketal hydrobromide and / or solvate of organic solvent are isolated from the resulting product. the crystalline water and / or the solvent solvate is then removed, if desired, by dehydration with 1-2 mol of dehydrating mixture of the hemiketal hydrobromide III and the 11a-chloro-6-deoxy-6-demethyl-IV compound (IV). 6-Methylene-5-oxytetracycline is isolated as its salt. Acetone containing from 0 to 10% v / v water is preferably used as a solvent for the hemiketal salt formation. Acetone may be partially or completely replaced by methanol.

The present invention is based on the discovery that the novel salt of formula III having valuable properties can be advantageously used in the synthesis of tetracycline backbone antibiotics.

The compound of formula (II) is prepared in a manner known per se from the oxytetracycline of formula (I) obtained by fermentation with a suitable halogenating agent (Hungarian Patent No. 150,507). Thus, oxytetracycline is reacted with a chlorinating agent in a water-miscible, inert organic solvent at a temperature of (-25) to 50 ° C, at a pH close to the isoelectric point of oxytetracycline, and the product is isolated by dilution with water (2,984,686 and 3,200). No. 149, U.S. Pat.

It is also known that the hemiketal base of formula (II) is converted, after isolation, to the hydrochloride with anhydrous hydrochloric acid (Belgian Patent 777 356, German Patent Publication No. 2,131,944).

An improved version of the former is provided in Resolution 170.051. U.S. Patent No. 5,123,123, which chlorinates 5-oxytetracycline in a water-containing acetone system at -40 ° C and then, after a few minutes' reaction, forms the hydrochloride salt of the hemiketal base II with anhydrous hydrochloric acid.

The 1α-chloro-5-hydroxytetracycline-6,12-hemiketal base or its hydrochloride salt of formula IIa is subjected to dehydration when used in the synthesis of doxycycline, most often treated with hydrogen fluoride or sulfuric acid or demethyl-6-deoxy-6-methylene-5-oxytetracycline or acid addition salts thereof.

It is known that the base structure of the hemiketal of formula II is rather unstable. Methods for its preparation largely take this into account when they are generally employed at low temperatures and, after a rapid chlorination reaction, aim to provide conditions under which the product crystallizes out of solution in a short time, thereby avoiding immediate decomposition processes in the dissolved state.

Also, due to the high sensitivity of the product, rapid filtration from the reaction mixture and rapid and complete removal of mother liquor residues are important. From this point of view, a very unpleasant property of the hemiketal base of formula (II) is the well-known poor filterability. Residual impurities favor the subsequent decomposition processes of the finished product, which, according to operational experience, can lead to complete decomposition of the material. Furthermore, since no method for purifying the molecule due to its high sensitivity is known, the quality problems of the hemiketal base of formula (II) also persist during the next delicate dehydration step of the synthesis and result in variations in the yield and quality of the product prepared therein. Another problem is that the hemiketal base of formula (II) generally contains 10% water, which corresponds to three "crystalline water" per molecule. This high water content greatly contributes to the instability of the compound.

The aforementioned dehydration reaction, which is based on the hemiketal base of formula (II), under very drastic conditions, is very harmful to health, such as safety acids. hydrogen fluoride, chlorosulphonic acid or sulfuric acid, or other dehydrating agents such as dehydrating agent formic acid and chlorosulphonic acid. (Hungarian Patent No. 188,367).

Therefore, it is not indifferent how much dehydrating agent is used for dehydration

-2HU 13300 »must be used. For a starting material containing 10% water, this is at least four times the amount of the dehydrating agent that is theoretically required.

In view of all these facts, it is understandable why a solution has been developed which produces a purer, more stable product from the hemiketal base of formula (II), which crystallizes with 2 moles of water in the form of hydrochloric acid salt.

However, hydrochloric acid formation is generally difficult to combine with chlorination for solubility reasons. Therefore, the hemiketal base of formula (II) must first be isolated and then salt formation can be carried out under anhydrous conditions.

The already mentioned 170.051. a Hungarian patent combines chlorination with salt formation.

However, this process is difficult to implement on an industrial scale, and occurs under extreme conditions. One problem is that the chlorination takes place in the presence of water, but the hemiketal hydrochloric salt formed during subsequent salt formation is very soluble in water. It is also a disadvantage that the decomposition of the hemiketal base (II), which is primarily formed during the instant chlorination and which is present in solution, starts almost immediately at the moment of formation. To stop this, it is essential that the entire mass of hydrochloric acid required for salt formation reaches the reaction mixture without delay, since decomposition stops in an acidic medium. Since aqueous or alcoholic hydrochloric acid cannot be used due to solubility conditions, it is only possible to dry the dry hydrochloric acid gas in acetone and add the resulting hydrochloric acid acetone to the reaction mixture.

However, this method is unusual from an industrial point of view and is not chemically recommended as it is well known that ketones show autocondensation reactions under the influence of strong mineral acids. If, for example, in chilled acetone, hydrogen chloride gas is passed, then mesityloxide and then foron are formed.

Alternatively, (GD 219021), the 5-oxytetracycline hydrochloride salt is chlorinated with benzenesulfonium chloroamide sodium (Neomagnol) in aqueous acetone, and the reaction mixture is treated with a mixture of hydrochloric acid and acetone in the form of Ia-chloro (III). The hydrochloride salt of -5-oxytetracycline-6,12-hemiketal is obtained which, however, contains 14% by volume of sodium chloride due to unfavorable solubility conditions.

We have been looking for a solution to the problem outlined above, which is well suited for large-scale production.

In other words, we searched for a salt, or a derivative thereof, of the 11a-chloro-5-hydroxytetracycline-6,12-hemiketal of formula (II), which is stable, easy to prepare, and the methacycline or methacycline. can be well integrated into the synthesis of doxycycline and can be used to develop a technology that avoids the preparation of the hypersensitive hemiketal base of formula II.

The present invention is based on the discovery that by treating the hemiketal base (II) in a water-miscible organic solvent, preferably ethanol or acetone, with a concentrated aqueous solution of hydrobromic acid, 11a-chloro-5-hydroxytetracycline (III) is obtained in near quantitative amounts. 6,12-hemyl ether hydrobromide.

The hydrobromide of formula (III) according to the present invention has all the properties which make it suitable for solving the problem outlined above.

Due to its stable, favorable solubility properties it is easy to prepare a pure substance. A particular advantage is that it crystallizes with up to one mole of crystalline water, as opposed to the hemiketal base of formula (II), which is usually three, and its hydrochloric acid salt, which contains two crystalline waters. The low water content is probably related to the good stability and filtration properties of the new salt.

Its use in the dehydrating step of doxycycline (or methacycline) synthesis dramatically reduces the amount of dangerous dehydrating agent required, which greatly increases the safe feasibility of the reaction and creates a favorable position for 1α-chloro-6-demethyl-6-deoxy-6-methylene- 5-hydroxytetracycline or its acid addition salts.

The novel salt of formula (III) is particularly useful in the synthesis of methacycline, hydrobromide salt and / or doxycycline hydrobromic salt, which are pharmaceutically equivalent to the corresponding hydrochloric acid salts.

The preparation of the compound of formula (III) from the hemiketal base of formula (II) is simpler and less expensive than that of the commonly known and used hydrochloric acid salt.

The discovery of the novel salt of formula (III) has made it possible to develop a synthesis starting from the 5-oxytetracycline or acid addition salts of formula (I) which solves the 1-chlorination and salt formation in a single step thus avoiding the preparation of the hemiketal base of formula (II) which is known to be required.

According to the present invention, the yield is 85-95% based on the 5-oxytetracycline base of formula (I).

This method compares with the above-described 170.051. with a higher yield, taking into account the fact that the yield (78.4%) reported therein relates to the 5-oxytetracycline hydrochloride salt, which is also obtained from high-quality 5-oxytetracycline in only 90-95% yield. can be solved. In fact, it is between 70.6% and 74.5%.

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It has been very important for the success of the one-step synthesis from 5-oxytetracycline that the bromide salt of oxytetracycline hydrogen is particularly useful as a starting material for la-chlorination for solubility reasons. This is also interesting because only the appropriate hydrochloric acid salt is used in the synthesis of tetracycline skeletal antibiotics.

The 5-oxytetracycline-HBr salt, unlike the corresponding hydrochloric acid salt, is highly soluble in acetone, so that chlorination can be carried out even under anhydrous conditions, providing an ideal position for the separation of the water-soluble salts of the chlorinated product.

However, it should be noted that the formation of the 5-oxytetracycline-HBr salt is a more delicate task than the hydrochloric acid salt.

Choosing the right chlorinating agent is also an important consideration. N-chlorosuccinimide is most often used as a chlorinating agent, but the use of the much cheaper benzenesulfonium chloramide sodium (hereinafter "Neomagnol") should be considered when developing an economical industrial process.

However, working with Neomagnol is not as easy as using N-chlorosuccinimide.

There are three basic considerations for la-chlorination of 5-oxytetracycline I:

1.) Chlorination takes place only in the pH range of 6-8.

2.) The chlorinating agent should be added gradually to the 5-oxytetracycline as much as possible, since multiple chlorinated derivatives are readily formed.

3.) Chlorination takes place very quickly and produces quite a lot of heat.

When N-chlorosuccinimide is used, the 5-oxytetracycline base is liberated from the acid addition salt of 5-oxytetracycline and then chlorinated with N-chlorosuccinimide as the reaction proceeds.

However, in the case of Neomagnol the situation is different, since the same molecule (Neomagnol) has an indissociable basic and chlorinating properties, and therefore, optimally, the reaction partners must be brought together; to ensure that Neomagnol can perform both functions at the right time and in the right way. Given that both la-chlorination and the conversion of anhydrous 5-oxytetracycline base, which is liberated in situ, to 5-oxytetracycline dihydrate insoluble in the medium is a very rapid process, the neomagnol is readily available for reaction in the minutes of chlorination, or it must be in an easily dissolvable state. Since Neomagnol is not soluble in the acetone commonly used as a medium to date, sufficient water is required for chlorination to take place. However, the presence of water interferes with salt formation immediately after chlorination as discussed above.

Surprisingly, we have found that alcohols, especially methanol, which is a very good solvent for Neomagnol, are an excellent medium, under suitable conditions, for the simultaneous implementation of la-chlorination and subsequent salt formation, although (II) and It is not considered to be an inert solvent for the compounds of formula (III). In fact, in methanol, the compounds of formula (II) and (III) are degraded to a degree dependent on pH and, of course, temperature. The degradation process is already significant in the neutral pH range; however, it decreases towards the acidic range and no longer occurs at pH = 1. Accordingly, it has been reported in the literature that methanol has never been used as a medium for the 5-oxytetracycline-la-chlorination.

When using methanol or methanol-acetone, chlorination has a slower purge compared to aqueous systems, which has several advantages in commercial operation. On the one hand, the amount of heat released per unit of time is reduced, which is easier to discharge, and on the other hand, it is possible to add the reactants over time.

In addition, when methanol is used instead of water, the salts of the hemiketal of formula (II) are more readily recovered in solid form using less precipitating solvents.

We were surprised to find that while the chlorination in the water-acetone system, the subsequent hydrobromide salt formation was satisfactory at 40-50 ° C, the methanol-acetone was used at -20 and -10 ° C. The hydrobromide salt of the product which crystallizes from the solution in the form of a hydrate or an organic solvent solvate depending on the content of water and organic solvent in the reaction mixture. The product containing water and organic solvent is dried or treated at 25-50 ° C with ethanol or acetone to give the hydrobromide III, and the concentrated hydrobromide aqueous ethanol to give the hydrobromide monohydrate III.

The salt of formula (III) containing water and the organic solvent is converted to a hydrate of the hydrobromide of formula (III) within a few days to a few weeks depending on the conditions. Organic solvent solvates and hydrates are well distinguished by their infrared spectra, so that interconversion of the various forms can be observed spectrophotometrically.

The product of formula (III) containing crystalline water can be reduced to 0.1-0.2% without decomposition by drying in vacuo over phosphorus pentoxide or by vacuum drying in a vacuum oven at 70-80 ° C for several hours.

Starting from the prepared hemiketal of formula II, the lla-chloro-5-hydroxytetracycline-6,12-hemiketal of formula II is hydrobromide-4EN 199389 A

The preferred medium for the formation of its salt is acetone, alcohols or ethyl acetate. The best temperature range for salt formation is 35-40 ° C. For solubility reasons, it is advisable to use a concentrated aqueous solution of hydrogen bromide.

For the dehydration of the crystalline water form of the compound of formula (III), 1 to 1.5 moles of chlorosulfonic acid are used, or 2 moles of the monohydrate.

In the case of organic solvent solvates, 2.5 to 3 moles of dehydrating agent are required, but since the acetone present interferes with the reaction (reacts with the chlorosulfonic acid), the 11a · -chloromethacycline p-toluenesulfonate of formula IV can be obtained . For this reason, the organic solvent solvate of the compound of formula (III) may be converted to the corresponding anhydrous or monohydrate form by drying or solvent treatment before dehydration.

The details of the invention are set forth in the Examples.

Example 1 1-Chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate g (0.1 mole) of 1α-chloro-5-hydroxytetracycline-6,12-hemiketal 3H ₂ O was suspended in 150 ml of acetone. . 24 ml of a 52% aqueous hydrobromic acid solution are added dropwise with stirring at 35-40 ° C. The reaction is exothermic, so cold water cooling provides the desired temperature of 35-40 ° C. The starting material gradually dissolves in solution and at the same time crystallization of the product begins. After stirring for a further 30 minutes at 40 ° C, the precipitated white crystals were cooled to 10 ° C, filtered, washed with acetone and dried at 40 ° C in vacuo. 53.4 g of product are obtained, which is 90% of the calculated amount.

Elemental Analysis: - C ₂₂ H ₂₃ ClN ₂ O.HBr.H ₂ OC% H% N% 01 Br ' ^- ' Calculated 44.34 4.40 4.70 5.97 13.46 Found 45.06 4.41 4, 98 6.05 13.55

Water content (measured by Karl-Fischer method):

Calculated: 3.13%, found: 3.20%.

UV Spectrum: The product exhibits an absorption maximum at 0.01η hydrochloric acid methanol at 265 nm and 340 nm.

OTC contamination: 1% by TLC.

Example 2 IIa-chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate.

g (0.1 mol) of 1α-chloro-5-hydroxytetracycline-6,12-hemiketal. 3H ₂ O was suspended in 200 ml of ethanol. 24 ml of a 52% aqueous hydrobromic acid solution are added dropwise with stirring at 35-40 ° C. The reaction is exothermic, so cold water cooling provides the desired temperature of 35-40 ° C. The starting material is gradually dissolved in solution and at the same time crystallization of the product begins. After cooling for 30 minutes at 40 [deg.] C. and then at 10 [deg.] C., the precipitated crystals are filtered off, washed with acetone and dried at 40 [deg.] C. in vacuo. 52.2 g of product are obtained, which is 88% of the calculated amount. It has the same quality as the material prepared in Example 1.

Example 3

Ia-Chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate (5 g) (0.05 mol) was suspended in 5 ml of acetone, 120 ml of water and 4 ml of 63% aqueous hydrogen bromide. A solution is obtained which is stirred for 15 minutes at 45 ° C and then cooled to -40 ° C. Diluted with 150 ml of acetone, while maintaining the temperature at -40 ° C, 10 ml (0.07 mol) of triethylamine are added and 6.5 g (0.064 mol) of N-chlorosuccinimide are added over 2-3 minutes. After 1-2 minutes, acidify with 12 ml of 63% aqueous hydrogen bromide and heat to 40-50 ° C. Crystallization of the product begins at 40 ° C. After stirring for half an hour at 40-50 ° C, it is filtered at this temperature, washed with acetone and dried at 40 ° C.

Weight: 24.35 g (82%). The product is of the same quality as that of Example 1.

Example 4

II? -Chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate.

5-Hydroxytetracycline dihydrate (g, 0.05 mol) was suspended in a solution of acetone (120 mL) and water (5 mL), 63% aqueous hydrobromic acid (4 mL) was added and stirred at 45 ° C for 15 min. It is then cooled to -10 ° C, diluted with 150 ml of acetone and, while still being maintained at -10 ° C, 10 ml (0.072 mol) of triethylamine are added dropwise. After 0.5 minutes, 8.5 g (0.064 mol) of N-chlorosuccinimide are added over 2-3 minutes and acidified with 12 ml of 63% aqueous hydrogen bromide at -10 ° C under cooling. After stirring at this temperature for 15 minutes, water (5 ml) was added and the product crystallized by heating to 40-50 ° C. It is filtered at 40-50 ° C, washed with acetone and then with chloroform, and dried at 40 ° C. Weight: 25.24 g (85%). The product is of the same quality as the material prepared in Example 1.

Example 5 1-Chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate 25 g (0.05 mol)

5-Hydroxytetracycline dihydrate is suspended in a solution of 120 ml of acetone and 4 ml of water, 4 ml of 65% aqueous hydrogen bromide are added and the mixture is stirred at 45 ° C for 15 minutes. Then cooled to -40 ° C, diluted with 130 ml of acetone and continued to keeping the system at -40 ° C for a half minutes a solution of 15 g (0.062 mole) of benzene szulfonklór amide nátrium.1,5 _H2 O in a solution of 16 ml of water and 40 ml of acetone. After stirring for 4-5 minutes at -40 ° C, 12 ml of 63% aqueous hydrogen bromide are added,

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50 ° C. After stirring for half an hour at this temperature, the precipitated crystalline product was filtered off, washed with acetone and dried at 40 ° C. Weight: 25.5 g (86%). The product is of the same quality as the material prepared in Example 1.

Example 6 1-Chloro-5-hydroxytetracycline-6,1-2-hemiketal hydrobromide monohydrate.

5-Hydroxytetracycline hydrochloride (0.05 mol) was dissolved in acetone (120 ml) and water (13 ml) and cooled to -20 ° C. 15 g (0.062 mol) of benzenesulfone chloramide sodium-1.5H ₂ O (Neomagnol) are added and stirred at -10 - (- 15) ° C for 3 minutes. A solution of 12 ml of 63% aqueous hydrobromic acid and 150 ml of acetone cooled to -10 ° C is added and stirred at this temperature for 15 minutes.

Meanwhile, the precipitated sodium chloride is filtered off and the filtrate is stirred for 30 minutes at 45 ° C, whereupon the product crystallizes out. After cooling to 0 ° C, it is filtered, washed with acetone and dried at 40-50 ° C.

Weight: 19.3 g (65%).

It has the same quality as the material prepared in Example 1.

Example 711a-Chloro-6-deoxydemethyl-6-methylene-tetracycline-p-toluenesulfonate.

59.4 g (0.1 mol) of lla-chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate are suspended in a mixture of 50 ml of 98% formic acid and 100 ml of dichloromethane. At -10 [deg.] C., a solution of chlorosulfonic acid (13.3 mL, 0.02 mol) in dichloromethane (15 mL) was added dropwise.

After stirring for 30 hours at 30 ° C, methanol (60 ml) was added dropwise while cooling, keeping the temperature below 30 ° C. The reaction mixture was evaporated and the residue was taken up in 200 ml of acetone and 38 g (0.2 mol) of p-toluenesulfonic acid was added. After heating to reflux, the product precipitates, which is filtered off, washed with acetone and dried.

Weight: 63.4 g, 95% of the calculated amount. Mp: 181-193 ° C.

Elemental analysis: C ₂₂ H ₂ , C 1 N ₂ O ₈ .C ₇ H ₈ O ₃ SH ₂ O

C% H% N% Cl S Calculated: 52.21 4.69 4.20 5.32 4.81 Found: 52.53 4.83 4.33 5.49 4.62

Water content (Karl-Fischer method): 2.70%, found: 2.65%. U.V. Spectrum: The product exhibits absorption maxima at 270 and 372 nm in 0.01N hydrochloric acid methanol.

Example 8 Preparation of la-chloro-5-hydroxy-tetracycline-6,12-hemiketal hidrogénbromidaceton · 1/2 H ₂ O.

5-Hydroxytetracycline dihydrate (0.05 mol) was suspended in a solution of 160 ml of acetone and 3 ml of water, 4 ml of 63% aqueous hydrogen bromide were added and the mixture was stirred at 45 ° C for 15 minutes. 30 ° C.

g (0.062 mol) of chloro-benzene-sulfonic acid amide sodium 1.5 H ₂ O (Neomagnol) dissolved in 50 ml of methanol and cooled to -30 °.

The 5-hydroxytetracycline hydrobromic acid salt solution was added dropwise to a suspension of neomagnol in methanol for 20-30 seconds while the temperature rose to -10 ° C without cooling. Chlorination was carried out at this temperature for 5 minutes while a thick precipitate formed. After 5 minutes, 12 ml of 63% aqueous hydrobromic acid are added, whereupon the solid phase dissolves and the temperature rises to ~ 0 ° C. After cooling to -10 ° C and stirring at -10 ° C for 30 minutes, the crystalline product precipitated in the meantime was filtered, washed with acetone and dried at room temperature.

Weight: 28.95 g (90%).

Elemental Analysis C ₂₂ H ₂₃ ClN ₂ O ₉ .HBr.C ₃ H ₆ Ox

X 1/2 H ₂ O

Calculated for CΗ N Cl: 46.7% 4.86% 4.36% 5.51% Found: 46.67 4.78 4.48 5.40

Br calculated: 12.43% found: 12.30

Solvent content by gas chromatography

Acetone content: 8.7% (calculated 9.15%)

II.V. spectrum

The product exhibits an absorption maximum at 265 and 340 nm in 0.01N HCl methanol. Water content (Karl-Fischer method): 1.40% found: 1.30%

OTC contamination by TLC <1% Mammalian content <0.1%

Example 9

Ila-chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide.

Example 8 (57.9 g)

200 ml abs. The reaction mixture was stirred in ethanol at room temperature for 30 minutes, then filtered, washed with a little ethanol and dried. Weight: 51.5 g (89%).

Analysis:

Water content (measured by Karl-Fischer method) 1%

Bromide ion content 13.7% (calculated 13.88%)

SCI: 5.7% (calculated 6.16%).

Example 10

II? -Chloro-6-deoxy-6-demethyl-6-methylene-tetracycline-p-toluenesulfonate.

57.6 g (0.1 mol) of lla-chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide salt are suspended in a mixture of 50 ml of 98% formic acid and 100 ml of dichloromethane. A solution of chlorosulfonic acid (10 mL, 0.15 mol) in dichloromethane (10 mL) was added dropwise at -10 ° C.

stirring at 0 ° C for 1 hour, then at 30 ° C for 3 hours, followed by cooling to

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While keeping below 30 ° C, 60 ml of methanol are added dropwise. Thus, by converting the formic acid present to methyl formate, the solvent mixture is distilled off, the residue is taken up in 230 ml of acetone, and 38 g (0.2 mol) of p-toluenesulfonic acid are added. After heating to boiling point, the product precipitates, which is filtered after cooling for 30 minutes to 10 ° C, washed with acetone and dried.

Weight: 60 g (90%)

The product is of the same quality as the material prepared in Example 7.

EXAMPLE 11 α-Chloro-5-hydroxytetracycline-6,12-hem icetal hydrobromide monohydrate.

5-Hydroxytetracycline dihydrate (0.05 mol) was suspended in a solution of acetone (60 ml) and water (3 ml), hydrobromic acid (63 ml, 4%) was added and stirred at 45 ° C for 15 minutes and then cooled to -30 ° C. ° C. 15 g (0.062 mol) of benzenesulfonate chloride-1.5 H ₂ O (Neomagnol) are dissolved in 50 ml of methanol, 0.5 ml of triethylamine are added and cooled to -40 ° C.

The 5-hydroxytetracycline hydrobromic acid salt solution was added dropwise to a methanolic suspension of neomagnol over a period of 20 to 30 seconds while the temperature rose to -10 ° C without cooling. Chlorination was carried out at this temperature for 5 minutes while a thick precipitate formed. After 5 minutes, 12 ml of 63% aqueous hydrogen bromide are added, whereupon the solid phase dissolves and the temperature rises to ~ 0 ° C. After cooling to -10 ° C and stirring at -10 ° C for 30 minutes, the crystalline product which had precipitated in the meantime was filtered, washed with acetone and dried at room temperature.

Weight: 26.9 g (90%).

The quality of the product is l ·. identical to the material prepared according to example.

Example 12 1-Chloro-5-oxytetracycline-6,12-hemiketal hydrobromic acid. 1/2 H ₂ Ol / 2 Acetone 1/2 Methanol.

5-Oxytetracycline dihydrate (0.05 mol) was suspended in a solution of acetone (60 ml) and water (3 ml), 63% aqueous hydrobromic acid (4 ml) was added and stirred at 45 ° C for 15 minutes and then cooled to -20 ° C. ° C.

Neomagnol (g, 0.062 mol) was dissolved in methanol (200 ml) and cooled to -20 ° C.

The 5-oxytetracycline hydrobromide solution was added to the Neomagnol methanolic solution over 1 minute with vigorous cooling, keeping the temperature below -10 ° C. 4 min chlorinated -10 ^e C and then cooling to 12 ml of an aqueous hydrobromic acid solution 63% was added and stirred for 30 minutes at -10 ° C. The crystals that had precipitated in the meantime were filtered, washed with acetone cooled to -10 ° C, and dried at room temperature.

Weight: 25.2 g (80%).

Analysis

C ₂₂ H ₂₃ ClN ₂ 0g-HBr 1/2 C ₃ H ₆ O · 1/2 CH ₃ OHX Xl / 2 H ₂ O

C H Cl N calcd: 45.76% 4.80% 5.60% 4.44% found: 45.34% 4.90% 5.40% 4.60%

Br Calculated: 12.68% Found: 12.40%

Water content (calculated by Kari Fischer method): 1.4% found: 1.4%

Example 13 la-chloro-5-hydroxytetracycline-6,12-hemiketal hydrobromide monohydrate.

No. 11 The starting material was 23 g (0.05 mol) of anhydrous 5-oxytetracycline. The quantity and quality of the product obtained are all. is the same as in example.

Claims (3)

1.) Process 1-la-chloro-5-oxytetracycline-6,12-hemiketal hydrobromide of formula III, a hydrate thereof and / or a solvate of an organic solvent and optionally a la-chloro-6 of formula IV: for the preparation of deoxy-6-demethyl-6-methylene-5-oxytetracycline and its salts from the 5-oxytetracycline or its hydrate of formula I by formation of an acid addition salt followed by the addition of a water-water-miscible organic solvent, benzene sulfone by chlorination of the chloramide with sodium (neomagnol) or N-chlorosuccinimide, followed by reacting the resulting la-chloro-5-oxytetracycline-6,12-hemiketal (II) or its hydrate with hydrogen halide, and dehydrating the resultant salt optionally with a dehydrating mixture of chlorosulfonic acid and formic acid, characterized in that the 5-oxytetracycline or hydrate of the formula (I) with an aqueous hydrochloric acid or preferably with hydrobromic acid in acetone, preferably hydrobromide is formed which is chlorinated without isolation, in the presence of methanol for the hydrobromide, to give 11a-chloro-5-oxytetracycline-6,12-hemiketal of formula II, preferably without isolation from the reaction mixture, with concentrated aqueous hydrobromic acid. treating at -20 to -60 ° C and isolating the crystalline precipitated lla-chloro-5-oxytetracycline-6,12-hemiketal hydromide hydrate and / or solvate of the organic solvent. crystalline water and / or solvent solvate is removed from the product, if desired, and then, if desired, dehydrated with 1 to 2 moles of dehydrating mixture to the hemiketal hydrobromide (III) and the 11a-chloro-6-deoxy (IV) -6-Demethyl-6-methylene-5-oxytetracycline is isolated as its salt. 2. A process according to claim 1, wherein the water content of the reaction mixture used for chlorination is from 0 to 10% by volume. -7HU 199389 A 3. A process according to claim 1 or 2, characterized in that 5-oxytetracycline hydrobromide is chlorinated in a 1: 1 mixture of methanocacetone with benzenesulfonylchloramide sodium, and the resultant lla-chloro-5 is obtained. - 5 -oxytetracycline-6,12-hemiketal is treated with concentrated aqueous hydrobromic acid at -20 ° C to + 10 ° C and isolated the crystalline precipitated salt of the Formula III hydrate and / or solvate.