MXPA00000354A - Organic compounds - Google Patents

Abstract

Erythromycin A oxime;in anhydrous and stable form;in the form of a solvate with non-halogenated organic solvent;and in the form of a hemihydrate, processes for its productions;and their use in the production of a semi-synthetic macrolide from the erythromycin type.

Description

ORGANIC COMPOUNDS The present invention relates to the synthesis of antibacterial macrolides, such as the erythromycin type, for example erythromycin A, for example roxithromycin, dirithromycin, clarithromycin, azithromycin, and the like. A compound useful in the production of antibacterial macrolides, such as those of the erythromycin type, for example, is described in U.S. Patent No. 3,478,014, ie a compound of the formula: OH CH, hereinafter referred to as erythromycin oxime A. Erythromycin A, for example, is a well-known antibacterial agent. The isolated erythromycin A oxime, for example in free base form, obtained according to known processes, can be obtained in an unstable form, for example it can be hygroscopic. We have now found the erythromycin A oxime in free base form, in a stable form, for example non-hygroscopic, for example a compound according to the present invention, can maintain a constant water content under normal environmental conditions, by example normal air humidity, for at least 24 hours. In one aspect, the present invention provides a compound of the formula I: - in anhydrous and stable form, or - in the form of a solvate with a non-halogenated organic solvent; or - in the form of a hemihydrate.

The non-halogenated organic solvent, as used herein, can form a solvate with a compound of the formula I, and can form a two-phase system with water. The non-halogenated solvent includes, for example, alkyl esters of acetic acid, preferably with alkyl of more than one carbon atom, for example of 2 to 8 carbon atoms, such as 2 to 6 carbon atoms, such as acetates of ethyl, propyl, and butyl, for example isopropyl acetate and normal butyl acetate; and alkyl ketones, for example dialkyl ketones, for example methyl butyl ketones, such as methyl isobutyl ketone. Mixtures of the individual solvents are included, for example as described above. The non-halogenated organic solvent, as used herein, means that the chemical formula of the organic solvent does not contain halogen atoms. In contrast to this, a halogenated organic solvent means that the chemical formula thereof contains at least one halogen atom. If not otherwise defined herein alkyl includes alkyl (1 to 12 carbon atoms), for example alkyl (1 to 8 carbon atoms), such as alkyl (1 to 6 carbon atoms), for example alkyl (1 to 4 carbon atoms). In the erythromycin A oxime, for example of the formula I, in the form of a hemihydrate, according to the present invention, it is possible to determine: a water content (Karl Fischer) of approximately 1.6 percent (theory: 1.19 percent; monohydrate; 2.35 percent), which may remain below 2.35 percent, for example 2 percent, after several hours, eg 24 hours or more, for example several days under conditions of half normal ambient , eg normal air humidity, an endotherm at 136 ° C in differential scanning calorimetry (heating rate of 10 ° C / minute), - a loss of 1. 15 percent of weight between 100 ° C and 200 ° C in thermal gravimetric analysis (theory: 1 19 percent.), A high content of E isomer, and BAJ or Z isomer content. A compound of the present invention, including, eg emplo, a compound of formula I in anhydrous and stable, and a compound of formula I in the form of a solvate with non-halogenated solvent, and a compound of formula I in the form of a hemihydrate, it can be obtained as follows: The erythromycin A oxime, for example, of the formula I, can be treated in a mixture of water and aromatic solvent; or - can be extracted in a non-halogenated solvent which can form a solvate with a compound of the formula I, and which is capable of forming a two-phase system with water; and a compound of the present invention can be isolated; and an isolated compound of the present invention treated with aromatic solvent, can be dried at temperatures of 50 ° C or higher. In another aspect, the present invention provides a process for the production of a compound of the formula I in the form of a solvate, which comprises: treating a compound of the formula I in a mixture of water and aromatic solvent, and isolating a compound of the formula I in the form of a hemihydrate; or extracting a compound of the formula I in a non-halogenated solvent, and isolating a compound of the formula I in the form of a solvate with non-halogenated organic solvent; and a process for the production of a compound of the formula I in anhydrous and stable form, which comprises drying a compound of the formula I in the form of a solvate with non-halogenated solvent, at temperatures of 50 ° C or higher. In the process of the present invention, a compound of the formula I in free base form, or in the form of a salt, for example a hydrochloride, and / or in the form of a solvate, such as a hydrate, preferably in the form of a salt, it can be contacted with a mixture containing water and an aromatic solvent in the production of a hemihydrate of the formula I, or in non-halogenated solvent, for example as defined above, for the production of a compound of the formula I in the form of a solvate with non-halogenated solvent; for example, a compound of formula I can be dissolved or suspended in a mixture containing water and an aromatic solvent or a non-halogenated solvent. The pH of a mixture obtained can be a pH in which a compound of the formula I is present in free base form, including, for example, a pH of 7.5 to 10.5, for example 9.0 to 10.0. The adjustment of the pH, for example, from 7.5 to 10, for example, if a compound of the formula I is in the form of a salt, can be carried out, for example, by the use of an appropriate base, for example the addition to a suspension or a solution of a compound of the formula I in a solvent. An appropriate base includes a base that is capable of releasing a compound of formula I in the form of a salt; including, for example, an inorganic base, such as a hydroxide, carbonate, alkaline bicarbonate, for example sodium, potassium; alkaline earth, for example calcium, magnesium; and of ammonium; and an organic base, such as ammonia and an amine, for example alkylamine, such as triethylamine or di-isopropylamine, a base may preferably be a hydroxide, for example sodium and ammonia; preferably in aqueous solution; for example in an aqueous solution of about 10 percent to 35 percent, such as 15 percent to 30 percent. For example, the base may be combined with a solution or suspension of a compound of the formula I in the form of a salt in water, for example mixed with an aromatic or non-halogenated solvent. An aromatic solvent, as used herein, includes an aromatic organic solvent, such as benzene, toluene, xylene, for example o-xylene, m-xylene, p-xylene; preferably toluene or xylene; and an aromatic solvent system, for example mixtures of individual aromatic solvents, for example as described above; preferably a mixture of o-xylene and / or m-xylene and / or p-xylene; and a mixture of aromatic solvents with one or more different organic solvents, for example an organic solvent that may be useful in organic chemistry. Preferably, in the suspension or solution of a compound of the formula I, the non-halogenated solvent is present without an additional non-halogenated organic solvent; optionally, there may be one or more, for example, non-halogenated organic solvents miscible or immiscible with water present; with the understanding that a two-phase system is formed with water in a mixture of solvents; and with the understanding that a compound of the formula I is obtained in free base form from the mixture in the form of a solvate with a non-halogenated solvent. Preferably, the aromatic solvent is present without additional organic solvent.; optionally, an organic solvent may be present, for example such as an organic solvent useful in organic chemistry, preferably a solvent whose chemical formula does not contain a halogen atom; provided that a compound of the formula I is obtained in free base form, in the form of a hemihydrate, after combination with a base; for example in an isolation step. The non-halogenated solvent can be used in an amount sufficient to dissolve a compound of the formula I, for example during an extraction of a compound of the formula I in the organic phase, which may depend on the solubilization characteristics of the solvent. Per gram of a compound of the formula I, there can be used, for example, from 2 milliliters to 20 milliliters and more, for example from 3 milliliters to 15 milliliters, such as from 5 to 12 milliliters of the non-halogenated organic solvent. The amount of non-halogenated organic solvent with respect to the amount of water may depend on the chemical nature of the organic solvent, and on the miscibility characteristics of the organic solvent with water. The scale of water and non-halogenated organic solvent used can be such that a two-phase system is formed. The appropriate amount of water and the amount of non-halogenated organic solvent can be easily determined. The amount of aromatic solvent is not critical, and includes a scale, for example, of about 0.5 milliliters, such as 3 milliliters, to 20 milliliters per gram of a compound of formula I; the amount of water in the case of using the aromatic solvent, is not critical, and includes a scale from traces of water in an aromatic solvent, example, which may be sufficient to form an erythromycin A oxime hemihydrate, up to an amount of water that causes the formation of a two-phase system with an aromatic solvent; or still higher amounts of water, such as from 0.1 to 100 parts (volume / volume) of water per part (volume / volume) of aromatic solvent; for example, from 0.5 to 10 parts (volume / volume). The temperature in a mixture of a compound of formula I with water and aromatic or non-halogenated solvent may be less than, about, or greater than room temperature; such as from about 0 ° C to about 60 ° C, for example from 0 ° C to 60 ° C; such as from 10 ° C to 50 ° C; for example from 20 ° C to 50 ° C in the case of using aromatic solvent; and, for example, at room temperature in the case of using a non-halogenated solvent. The erythromycin A oxime in the form of a salt, for example a hydrochloride, for example as it is useful as a starting material in a process of the present invention, is known, and can be obtained by a conventional process. A mixture of erythromycin A oxime, water, and aromatic or non-halogenated solvent obtainable according to the present invention can be stirred, for example in order to achieve a uniform mixture. In the case of using a non-halogenated organic solvent, and the production of a solvate of a compound of When the formula I is dissolved in a non-halogenated solvent, a compound of the formula I can be dissolved in the organic phase; the organic phase can be separated from the aqueous phase, for example as is conventional, and optionally dried, for example as is conventional, for example, by the addition of a drying agent, such as sodium sulfate, for example anhydrous, and the solvent can be removed, for example partially; for example by distillation, for example under reduced pressure. The precipitation of a compound of the formula I in the form of a solvate with non-halogenated solvent can be presented, and the precipitate can be isolated as usual, for example by filtration. A highly pure solid compound of the formula I can be obtained in the form of a solvate having a low Z-isomer content, for example in a stable form, for example non-hygroscopic. A compound of the formula I in the form of a solvate with non-halogenated organic solvent according to the present invention can be a true solvate composed of about one molecule of solvent per molecule of a compound of the formula I, and can be anhydrous and stable under normal environmental conditions, for example normal air humidity. A solvate of the present invention provides an intermediate in a surprisingly high purity, for example with a low Z-isomer content, such as less than 2 percent, and is useful, for example, as such, in reactions of a compound of the formula I. The content of water must be less than 1 percent, even less than 0.3 percent, such as 0.2 to 0.9 percent, for example from 0.3 to 0.6 percent, and the solvate may not be hygroscopic. A compound of the formula I in the form of a solvate with non-halogenated organic solvent according to the present invention, can be stable, and can be dried, for example under vacuum, for example at temperatures down to below 50 ° C, example from 20 ° C to approximately 45 ° C. A drying temperature scale for an isopropyl acetate solvate of 20 ° C to 35 ° C, and for a butyl acetate and a methyl isobutyl ketone solvate, from 30 ° C to 45 ° C under vacuum is preferred. If a solvate according to the present invention is dried, for example, at temperatures of 50 ° C and higher, for example under vacuum, for example at approximately vacuum temperatures of 50 ° C to 90 ° C, such as 60 ° C. C at 80 ° C, for example for an isopropyl acetate solvate of 65 ° C to 75 ° C, and for a normal butyl acetate and a methyl isobutyl ketone solvate, from 50 ° C to 70 ° C, a compound of the formula I can be obtained, for example in a non-solvated form, and in a surprisingly stable, for example non-hygroscopic, and anhydrous form. A compound of formula I in stable and anhydrous form is new, and can show an X-ray powder diffraction pattern, for example, depending on the type of dried solvate to obtain the compound of formula I in stable and anhydrous form: The X-ray powder diffraction pattern can be substantially as shown below in: Tables 1 and 1 (Table la is more detailed than Table 1), if a solvate of isopropyl acetate is dried; Tables 2 and 2a (Table 2a is more detailed than Table 2), if a normal butyl acetate solvate is dried; and Tables 3 and 3a (Table 3a is more detailed than Table 3), if a solvate of methyl isobutyl ketone is dried: Table 1 d (Á) I / lo d (Á) I / lo 12.98 1.00 6.57 0.37 8.58 > 0.34 5.64 0.36 8.31 0.69 4.40 0.37 6.76 0.39 Table 1a d (Á) I / lo d (Á) I / lo 15.18 0.26 6.57 0.37 12.98 1.00 5.64 0.36 10.16 0.30 5.23 0.21 8.58 0.34 5.16 0.27 8.31 0.69 4.81 0.25 7.53 0.22 4.40 0.37 6.76 0.39 Table 2 d (Á) I / lo d (Á)? /? 0 11.72 0.71 5.90 0.68 11.00 0.48 5.75 0.54 6.27 0.94 5.46 0.49 Table 2a d (Á) l / l0 d (Á) I / lo 18.90 0.36 6.27 0.94 12.64 0.40 5.90 0.68 11.72 0.71 5.75 0.54 1 1.00 0.48 5.46 0.49 Table 3 d (Á) I / lo d (Á)? /? 0 16.02 0.77 6.00 0.89 10.01 0.62 5.87 1.00 8.94 0.63 5.81 0.93 7.89 0.56 5.37 0.63 6.84 0.73 Table 3a d (Á) I / lo d (Á) I / lo 16.02 0.77 5.37 0.63 10.01 0.62 5.14 0.46 8.94 0.63 4.93 0.44 7.89 0.56 4.57 0.40 6.84 0.73 4.33 0.39 6.65 0.46 4.24 0.34 6.00 0.89 4.18 0.29 5.87 1.00 3.64 0.25 5.81 0.93 3.60 0.28 A compound of the formula I in stable and anhydrous form according to the present invention can be non-hygroscopic, for example it can maintain a water content of less than 1 percent, even after several hours, for example 24 hours, under normal environmental conditions, for example normal air humidity. It is surprising, because the known compounds of the formula I can not maintain a water content of less than 1 percent under normal environmental conditions, for example humidity of the air, but can recover water from the environment within ^ to »= a« ^ á ^ --- &sg - ^^ jM a short time, for example some hours, resulting in a water content that is greater than 1 percent. The X-ray powder diffraction pattern of a compound of formula I in a stable anhydrous form is different from the X-ray powder diffraction pattern of a known compound in an unstable anhydrous form, eg, hygroscopic, shown in the following Table 4: Table 4 d (Á) I / lo d (Á)? /? 0 15.13 0.27 6.39 0.38 12.96 0.21 6.01 0.65 9.92 0.47 5.71 0.34 8.78 0.46 5.08 0.56 7.61 1.00 4.88 0.32 6.93 0.34 4.58 0.28 6.76 0.39 4.35 0.23 In Tables 1, 1, 2, 2a, 3, 3a, and 4, d. denotes the interplanar separation, I / Io denotes the relative intensity, and Á denotes angstroms. In the case of using an aromatic solvent, and the production of a compound of the formula IV in the form of a hemihydrate, a mixture of erythromycin A oxime, water, and aromatic solvent, it can be stirred, for example, with the order to achieve a uniform mixture. The erythromycin A oxime in the form of a hemihydrate can be precipitated and can be isolated, for example, as is conventional, for example by filtration, centrifugation. A composition, for example isolated, of erythromycin A oxyme in the form of a hemihydrate, containing aromatic sol 5, for example up to about 30 percent (w / w), such as from about 1 to 15 One hundred (weight / weight) is novel. An isolated composition of erythromycin A oxime hemihydrate and aromatic solvent can be dried, for example under fast and light conditions, for example at temperatures of 50 ° C and above, for example under vacuum, for example at 50 ° vacuum temperatures. C at 90 ° C, to give erythromycin A oxime, for example a compound of formula I, in the form of a hemihydrate, in a stable, non-hygroscopic form, for example having a high content of, for example, the desired E-isomer, and a low content of, for example, the unwanted Z-isomer. The dry erythromycin A oxime in the form of a hemihydrate obtainable in accordance with the present invention may contain, for example, traces of, for example, residual aromatic solvent, such as 0.01 percent, for example, 0.05. percent up to about 1 percent, for example about 0.1 percent (weight / weight). In another aspect, the present invention provides a composition, for example isolated, containing aromatic solvent, for example in an amount of 0.01 percent to 30 weight percent / weight, and erythromycin A oxime, for example of the formula I , in the form of a hemihydrate. The advantage of a compound of formula I in the form of a solvate with non-halogenated solvent, and the processes for their production according to the present invention, can be as follows: the yields can be high. A compound of the formula I in stable and anhydrous form, can be obtained from a compound of the formula I in the form of a solvate, in a yield (test) higher than 96 percent, for example up to 99 percent and more. A compound of the formula I in stable and anhydrous form can be obtained from a compound of the formula I in salt form, in a total yield greater than 88 percent, for example up to 90 percent and more. Non-halogenated organic solvents are used. A single organic solvent can be used. A compound of the formula I in the form of a solvate with a non-halogenated solvent, and in a stable and anhydrous form, can be obtained in a high purity, for example with a low Z-isomer content. A compound of the formula I in the form of a solvate with non-halogenated solvent can be stable and non-hygroscopic. A compound of formula I in anhydrous and stable form has the following advantages: a) it can have a water content of less than 1 percent, even less than 0.3 percent, such as 0.2 percent to 0.9 percent; or example from 0.3 to 0.6 percent. This can be important in reactions where the presence of water should be avoided. b) it can be stable, for example non-hygroscopic, maintaining its water content below 1 percent for a long time under normal environmental conditions. c) It can be obtained in a high purity, for example the content of the Z isomer can be very low, for example such as less than 2 percent. A process according to the present invention, using the aromatic solvent and a compound of the formula I in the form of a hemihydrate, can have the following advantages: a compound of the formula I in the form of a hemihydrate can be stable and not hygroscopic, for example maintaining a water content below 2 percent even after several hours, for example 24 hours, under normal environmental conditions, for example normal air humidity. The yields can be high; for example, the erythromycin A oxime in the form of a hemihydrate can be obtained from a compound of the formula I in the form of a salt, for example hydrochloride, in a yield greater than 85 percent, for example greater than 90%. percent, such as even 93 percent and higher. - The production process is simple and does not require the slow extraction and concentration steps. A compound of the formula I in the form of a hemihydrate can be obtained in a high purity, for example, with a low content of the undesired Z isomer, for example less than 2 percent; and with a high content of the E-isomer, for example greater than 95 percent, for example even greater than 97 percent. The processes and a compound of the present invention can be used on an industrial scale. A compound of the present invention can be used as such, for example as an intermediate in the production of, for example, semi-synthetic macrolides, for example pharmaceutically active, such as the erythromycin type, for example A, such as roxithromycin, dirithromycin, clarithromycin, and azithromycin, preferably roxithromycin, clarithromycin, or azithromycin, for example by means of additional intermediates. In another aspect, the present invention provides a compound of formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, pai, used in the production of a macrolide of the eririfomycin type; and in another aspect, The use of a compound of the formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, in the production of a macrolide of the erythromycin type; and in another aspect, A process for the production of a macrolide of the erythromycin type, which comprises converting a compound of the formula I in stable and anhydrous form or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, in a macrolide of the erythromycin type, for example A. Roxithromycin can be obtained from the erythromycin A oxime, for example, by alkylation of the hydroxyl group of the oxime, for example by a process as is conventional, for example according to a method described in Patent Number ES 2,024,371, with a compound according to the present invention as a starting compound, instead of, for example, a known unstable compound, such as hygroscopic, of the formula I In a further aspect, the present invention provides a process for the production of roxithromycin, which comprises alkylating the hydroxyl group of the oxime group of a compound of the formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate. Clarithromycin can be obtained from the erythromycin A oxime, for example by methylation of the hydroxyl group in the 6-position of the compound of the formula I, and deoximation, for example by a conventional process. In a further aspect, the present invention provides a process for the production of clarithromycin, which comprises the steps of: (i) deoximation, and (ii) alkylation of the hydroxyl group in the 6-position of a compound of the formula I, characterized because a compound of the formula I is used in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, for example as an intermediate, for example as a starting material, example in the deoximation and / or alkylation of the hydroxyl group in the 6-position. Azithromycin can be obtained from a compound of the formula I, by means of a reconfiguration of Beckmann, and, for example, after the reduction, a 9-deoxo-9a-aza-9a-homoerythromycin A obtained can be methylated in the 9a-aza position, for example by a conventional process. In a further aspect, the present invention provides a process for the production of azithromycin, wherein a compound of formula I is reconfigured by means of a reconfiguration of Beckmann, and 9-deoxo-9a-aza-9a-homoerythromycin A obtained after the reduction it is methylated at the 9a-aza position, characterized in that a compound of the formula I is used in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, example as an intermediary, for example as a starting material, for example in a Beckmann reconfiguration reaction. The use of erythromycin A oxime in a stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate as a starting material in the production of a macrolide according to the present invention, it can have the following advantages: the starting material can be stable, the starting material can be pure, for example containing less than 2 percent of the Z-isomer. The starting material can contain only an organic solvent, for example residual. The starting material can be produced on an industrial scale in an economic and ecological process. The following non-limiting examples illustrate the invention. All temperatures are given in degrees Celsius, and are not corrected. The content of erythromycin A oxime in the starting material and in an epigomycin A oxime solvate with non-halogenated solvent, and in the erythromycin A oxime in the form of a hemihydrate (assay), is determined by liquid chromatography (HPLC). The solvent content in the erythromycin A oxime solvates with non-halogenated solvent, and the content of the aromatic solvent in a compound of the formula I in stable form and in the form of a hemihydrate, is determined by gas chromatography (upper space ).

Examples 1 and 2 (Differences of Example 2 with respect to Example 1 are indicated in parentheses) 20 grams (10 grams) of erythromycin A oxime in the form of a hydrochloride, with an erythromycin A oxime content, based on the Free base, 77.0 percent (82.6 percent), are suspended in a mixture of 110 milliliters (50 milliliters) of water and 125 milliliters of toluene (120 milliliters of xylene). The mixture is heated to 30 ° C-40 ° C (25 ° C-30 ° C), and the pH of the mixture is adjusted to 9.0-9.5 by the addition of 25 weight percent by weight aqueous ammonia. The suspension obtained is stirred at 40 ° C for 2 hours (30 minutes), and the pH is readjusted to 9.0-9.5. The erythromycin A oxime in the form of a hemihydrate is precipitated, filtered, washed with water and toluene (xylene), and dried at 65 ° C.

We obtain 14.5 which is 93 percent (92 percent) of the theory, and erythromycin A oxime in the form of a hemihydrate. HPLC content (assay): 98.5 percent (97 anhydrous base, water content - Karl (1.6 percent), water content after 3 days under normal environmental conditions: 1.6 percent (1.6 percent). Thermogravimetric analysis: weight loss between 100 ° C and 200 ° C: 1.15 percent.

Examples 3 to 6 General Procedure A) Erythromycin A oxime in the form of a solvate with a solvent as indicated under "Solvent" in Table 4 below A quantity of erythromycin A oxime in the form of a hydrochloride , in the grams indicated in Table 4 below under "Start (g)" (the erythromycin A oxime content is based on the free base, as indicated under "EA%" in Table 4 below), suspended in a mixture of a quantity of water, in the milliliters indicated under "Water" in Table 4 below, and an amount as indicated under "S (ml)" in milliliters in Table 4 below, of a solvent , as indicated under "Solvent" in Table 4 below, at a temperature in degrees Celsius as indicated under "T ° C" in Table 4 below. The pH is adjusted to a pH of 9.3 to 9.5 by the addition of 25 percent (weight / weight) aqueous ammonia. The mixture is stirred, and a two-phase system is obtained. The phases are separated, and the organic phase is dried over anhydrous sodium sulfate. The solid is filtered, and the filtrate is concentrated under reduced pressure. The solid erythromycin A oxime is precipitated in the form of a solvate, with a solvent as indicated under "Solvent" in Table 4 below, filtered, and dried overnight under vacuum at a temperature in degrees Celsius. it is indicated under "DT ° C" in Table 4 below, and is obtained in a yield in grams as indicated under "Yield" in Table 4 below, having a solvent content of a solvent as indicated under " Solvent "in Table 4 below, in% as indicated under" S-cont "in Table 5 below. The molar ratio of the solvent as indicated under "Solvent" in Table 4 below, and the erythromycin A oxime, is about 1: 1.

B) Erythromycin A oxime in stable and anhydrous form The erythromycin A oxime in the form of a solvate with a solvent as indicated under "Solvent" in Table 4 below, as obtained according to step A), is dried at a temperature as indicated under "DDT ° C" in Table 5 below, for a (approximate) time in hours as indicated under "Hours" in Table 5 below. The erythromycin A oxime in stable and anhydrous form is obtained in a gram yield as indicated under "Density" in Table 5 below, having an erythromycin A oxime content in% (assay) as indicated under "Assay "in Table 4 below, and a water content in% as indicated under"% Water "in Table 5 below. The total yield based on the erythromycin oxime hydrochloride A used as the starting material in% is as indicated under "Total Rend." In Table 5 below. The X-ray powder diffraction pattern is as given in the Table above, which is indicated under "TNo." in Table 4 below.

BOARDS

Claims (13)

1. RE IVI D ICATIONS
2. Erythromycin A oxime of the formula OH in anhydrous and stable form, or in the form of a solvate with a non-halogenated organic solvent; or - in the form of a hemihydrate. with the proviso that a solvate of a compound of formula I is excluded with isopropyl acetate 2. A compound of formula I according to claim 1, in stable and anhydrous form.
3. 3. A compound of the formula I according to claim 1, in the form of a solvate with a non-halogenated organic solvent that can form a two-phase system with water.
4. 4. A compound of the formula I according to claim 1, in the form of a hemihydrate. A process for the production of a compound of the formula I according to claim 1, in the form of a solvate, which comprises: treating a compound of the formula I as defined in claim 1, in a mixture of water and aromatic solvent, and isolating a compound of formula I in the form of a hemihydrate; or - extracting a compound of the formula I as defined in claim 1, in a non-halogenated solvent, and isolating a compound of the formula I in the form of a solvate with non-halogenated organic solvent; 6. A process for the production of a compound of the formula I in anhydrous and stable form, which comprises drying a compound of the formula I in the form of a solvate with non-halogenated solvent, at temperatures of 50 ° C or greater with the condition that a solvate of a compound of formula I is excluded with isopropyl acetate. 7. A composition containing aromatic solvent in an amount of 0.01 percent to 30 percent weight / weight, and erythromycin A oxime in the form of a hemihydrate. 8. A compound of formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, for use in the production of a macrolide of the erythromycin type with the proviso that that a solvate of a compound of formula I is excluded with isopropyl acetate. 9. The use of a compound of formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, in the production of a macrolide of the erythromycin type. 10. A process for the production of a macrolide of the erythromycin type, which comprises converting a compound of formula I in stable and anhydrous form or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate, in a macrolide of the erythromycin type. 11. A process for the production of roxithromycin, which comprises alkylating the hydroxyl group of the oxime group of a compound of formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate. 12. A process for the production of clarithromycin, which comprises the steps of: (i) deoximation, and (ii) alkylation of the hydroxyl group in the 6-position of a compound of the formula I, characterized in that a compound of the Formula I in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate. 13. A process for the production of azithromycin, wherein a compound of the formula I is reconfigured by means of a reconfiguration of Beckmann, and the 9-deoxo-9a-aza-9a-homoerythromycin A obtained after the reduction is methylated in the 9a-aza position, characterized in that a compound of the formula I is used in stable and anhydrous form, or in the form of a solvate with non-halogenated solvent, or in the form of a hemihydrate. N Erythromycin A oxime in anhydrous and stable form, or in the form of a solvate with a non-halogenated organic solvent; or in the form of a hemihydrate, processes for its production; and its use in the production of a semisynthetic macrolide of the erythromycin type.