Method for preparing and purifying derivatives of erythromycin

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.

EFFECT: improved preparing and purifying method.

28 cl, 11 ex

 

Description

The present invention relates to a method for producing derivatives of erythromycin.

A derivative of erythromycin, represented by formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), described, for example, in the Japan patent 6-56873 a and JP 9-100291 A. These compounds are known to possess the ability to enhance the motility of the gastrointestinal tract.

Methods of obtaining this compound are disclosed, for example, in Japan patent JP 6-56873 A, Bioorg. & Med. Chem. Lett., vol. 4(11), 1347 (1994), and in the Japan patent JP 9-100291 A.

However, methods of preparation, are disclosed in Japan patent JP 6-56873 and Bioorg. & Med. Chem. Lett., vol.4(11), 1347 (1994), are complex in implementation for industrial purposes, because they involve multiple stages and multiple use of column chromatography for purification. The Japan patent JP 9-100291 And outlines the concept of an improved method for obtaining compounds of the present invention of the formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which overcomes the above problems associated with the methods of obtaining, disclosed in Patan the e Japan JP 6-56873 and in Bioorg. & Med. Chem. Lett., vol.4(11), 1347 (1994). This publication describes the way in which the connection corresponding to the connection 5 of the present invention, carbamates in the presence of toluene, to obtain the compounds corresponding to compound 6 of the present invention. It also describes the way in which the connection corresponding to the connection 6 of the present invention, is subjected to catalytic hydrogenation in a hydrogen atmosphere using a catalyst of palladium on coal, with the connection corresponding to the connection 7 of the present invention. In addition, this publication describes a method in which a compound corresponding to compound 8 of the present invention, dissolved in methanol together with fumarate, and then crystallized by adding isopropanol, obtaining crystals of fumaric salt of compound 8 in accordance with the present invention. In addition, it describes the way in which crystals of fumaric salt of compound 8 in accordance with the present invention is dissolved in methanol, followed by addition of isopropanol, to obtain purified crystals fumaric salt of compound 8 in accordance with the present invention.

Since the connection corresponding to the connection 5 of the present invention, karbonitrirovanija dissolve in the e, described in Japan patent JP 9-100291 And encompasses the problem of slow interaction and the long time required for completion of the reaction, and also embodies the problem associated with the complexity and inefficiency of procedures, since the solvent must be replaced with a solvent miscible with water such as ethyl acetate for extraction of the reaction product, i.e., compounds corresponding to compound 6 of the present invention. Similarly, in the case where the connection corresponding to the connection 6 of the present invention, is subjected to catalytic hydrogenation in a hydrogen atmosphere using a catalyst of palladium on coal, there is a problem with the fact that the reaction product can be degraded, since the reaction mixture becomes acidic during the reaction. In addition, in the case where the connection corresponding to the connection 8 of the present invention, dissolved in methanol together with fumarate, and then crystallized by adding isopropanol, this method involves the problem that the resulting crystals are difficult to dry, and they contain large amounts of impurities. In addition, when the crystals fumaric salt compound corresponding to compound 8 of the present invention, dissolved in methanol followed by the addition of isopropanol, to obtain crystals of fumaric salt compound corresponding to compound 8 of the present invention, this method involves the problem that the resulting crystals are difficult to dry, and they contain large amounts of impurities.

Given the problems set forth above, the aim of the present invention is to provide an efficient way to obtain derivatives of erythromycin. The purpose of this invention is also a method of obtaining derivatives of erythromycin high quality.

As a result of multilateral and intensive studies for the implementation of the above purposes, the present invention has found an effective way to obtain derivatives of erythromycin and performed one aspect of the present invention. In addition, the authors of the present invention discovered a method of obtaining derivatives of erythromycin high quality and performed another aspect of the present invention.

Namely, the present invention relates to a method for producing fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes:

karbonitrirovanija the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group), to obtain the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV):

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3'-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II); and

the conversion of compounds of formula (II), fumaric salt;

where the compound of formula (I) interacts with CHLOROFORMATES in the presence of simple cyclic ether or ether carboxylic acid, to obtain the compounds of formula (III).

The present invention also relates to a method for producing fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes:

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES with obtaining the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV);

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3'-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II); and

the conversion of compounds of formula (II), fumaric salt;

where urethane groups of the compounds of formula (III) is removed in the presence of sodium bicarbonate, to obtain the compounds of formula (IV).

In addition, the present invention relates to a method for producing crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes:

the interaction of the compounds of formula (I)

(where R 1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV):

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3'-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II);

the conversion of compounds of formula (II) fumaric salt, to obtain the fumaric salt compounds; and

crystallization fumaric salt from a solvent containing alcohol;

where crystalline form is obtained by crystallization from isopropanol.

In addition, the present invention relates to a method for producing crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes:

the interaction of the compounds is of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV):

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3'-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II);

the conversion of compounds of formula (II), fumaric salt, to obtain the fumaric salt compounds;

crystallization fumaric salt from a solvent containing alcohol, to obtain the crystalline form; and

the recrystallization of the crystals from the solvent containing alcohol;

where the crystals precrystallization from isopropanol.

In addition, the present invention relates to a method for producing crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a bottom of the second alkyl group, and R2represents a lower alkyl group), which includes:

the interaction of the compounds of formula (I):

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV):

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3'-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II);

the conversion of compounds of formula (II) fumaric salt, to obtain the fumaric salt compounds;

crystallization fumaric salt from a solvent containing alcohol, to obtain the crystalline form; and

the recrystallization of the crystals from the solvent containing alcohol;

where the crystals precrystallization from isopropanol and then from a mixed solvent of methanol/isopropanol.

The present invention also relates to methods for which we obtain the crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes:

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with chloroformate, in the presence of simple cyclic ether or ether carboxylic acid, to obtain the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group), in the presence of sodium bicarbonate, to obtain the compounds of formula (IV):

(where R1represents a hydrogen atom or a lower alkyl group);

crystallization fumaric salts of the compounds of formula (II) from isopropanol, to obtain the crystalline form of fumaric with the connections; and

the recrystallization of the crystals from isopropanol and then from a mixed solvent of methanol/isopropanol.

The present invention also relates to a method for obtaining compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group), which includes the interaction of the compounds of formula (I):

(where R1represents a hydrogen atom or a lower alkyl group) with chloroformate, in the presence of simple cyclic ether or ether carboxylic acid.

In addition, the present invention relates to a method for obtaining compounds of formula (IV)

(where R1represents a hydrogen atom or a lower alkyl group), which includes the removal of all urethane groups of the compounds of formula (III):

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, and R4represents a hydrogen atom or urethane group), in the presence of sodium bicarbonate.

The present invention also relates to method p. the receipt of crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the crystallization of fumaric salts of the compounds of formula (II), of isopropanol.

In addition, the present invention relates to a method for producing crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the recrystallization of crystalline form of the fumaric salts of the compounds of formula (II) of isopropanol.

In addition, the present invention relates to a method for producing crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the recrystallization of the crystals fumaric salts of the compounds of formula (II), from isopropanol and then from a mixed solvent of methanol/isopropanol.

In addition, the present invention relates to a method for producing crystalline form of the fumaric salts of the compounds of formula (II):

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the crystallization of fumaric salts of the compounds of formula (II), from isopropanol, to obtain the crystalline form of the fumaric salt compounds, and the recrystallization of the crystals from isopropanol and then from a mixed solvent of methanol/isopropanol.

The following terms used here, as expected, have the meanings specified below, unless specified otherwise.

The lower alkyl group refers to C1-C6alkyl group with straight or branched chain, including methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, sec-boutelou group, tert-boutelou group, pentelow group and hexoloy group.

Lower alkyl group, R1preferably represents a methyl group, ethyl group, n-sawn group or isopropyl group, and particularly preferably a methyl group.

Lower alkyl group, R2preferably represents a methyl group, ethyl group, n-sawn group or isopropyl group, and especially preferably, the isopropyl group.

Chloroformiate refers to alkylchlorosilanes, including ethoxycarbonylphenyl, ethoxycarbonylphenyl, 2-fenilatilmalonamid, tert-butyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, p-methoxybenzeneboronic, p-nitrobenzisoxazole and benzyloxycarbonylglycine.

Urethane group refers to alkalicarbonate group, including methyloxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzenesulfonyl group and benzyloxycarbonyl group. Urethane group, R3and R4preferably represents benzyloxycarbonyl group, p-methoxybenzylideneamino group or allyloxycarbonyl group, and particularly preferably benzyloxycarbonyloxy group.

Examples of alcohols include methanol, ethanol, n-propanol, ISO-propanol, n-butanol, sec-butanol, tert-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, Cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propandiol, 1,4-butanediol and 1,5-pentandiol.

The solvent containing alcohol, refers to a solvent containing one or more alcohols. Examples include isopropanol and mixed solvent of methanol/isopropanol.

"The flask" means, in the sequence of reactions, each reaction product is intended for the next reaction without isolation and purification. The reaction in the same container, as defined here, includes not only the sequence of reactions carried out in the same reaction vessel, but also the sequence of reactions carried out in multiple reaction vessels (for example, by transferring the reaction mixture from one container to another), without isolation and purification. Preferably, the reaction in the same container is carried out in the same reaction vessel.

Used herein, the term "multiple number"relating to the material, as expected, indicates the mass ratio related to the material. For example, 2-fold the amount attributable to the material indicates the mass ratio of 2:1, related to the material. When the object of comparison is a liquid such as a solvent, "x number", referring to the material, as expected, indicates the ratio of the mass of liquid material. For example, 2-fold amount of solvent, relative to the material indicates the ratio of volume to weight of 2:1, solvent (for example, 2 liters) to a material (e.g., 1 kg).

Now, the method of receiving according to the present invention is described below.

In one embodiments, the method recip who were present invention includes a first stage of the interaction between the compounds of formula (I) with CHLOROFORMATES, obtaining the compounds of formula (III), second stage remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV), the third stage of alkylation of the nitrogen atom in the 3'-position of the compounds of formula (IV), to obtain the compounds of formula (II), the fourth phase conversion of compounds of formula (II), fumaric salt, to obtain the fumaric salts of the compounds of formula (II), and a fifth stage of recrystallization fumaric salts of the compounds of formula (II), to obtain the purified crystalline form of the fumaric salts of the compounds of formula (II).

In another embodiment, the method of receiving according to the present invention includes first, second, third and fourth stages discussed above. In another embodiment, the method of receiving according to the present invention includes first, second and third stage mentioned above. In another embodiment, the method of receiving according to the present invention includes a first stage mentioned above. In another embodiment, the method of receiving according to the present invention includes the second stage discussed above. In another embodiment, the method of receiving according to the present invention includes the fourth phase, discussed above. In the latter embodiment, the method of receiving according to the present invention includes a fifth stage discussed above.

In the case, including Pervoye second stage, in the production method of the present invention, the first and the second stage is preferably carried out in the same container. Similarly, in the case, including the second and third stage, these second and third stages are preferably carried out in the same container. In the case, including the third and fourth stages, these third and fourth stage is preferably carried out in the same container. In the case, including the fourth and fifth stages, these fourth and fifth stage is preferably carried out in the same container.

An example of a method of receiving according to the present invention is illustrated below.

The reaction scheme 1

in parallel with reaction scheme 1, below, an explanation is given for each stage.

First, compound 1, compounds of formula (I), interacts with chloroformate under basic conditions, to obtain the compound 2, the compound of formula (III) (the first stage). Chloroformiate used karbonatitovyi, preferably represents benzyloxycarbonyl, p-methoxybenzeneboronic or allyloxycarbonyl and particularly preferably benzyloxycarbonylamino.

Examples of bases suitable for use include inorganic bases such as sodium bicarbonate, potassium carbonate and hydroxide hydroxide is I, and tertiary amines, such as triethylamine and diisopropylethylamine. Preferred are inorganic bases, more preferred are sodium bicarbonate and potassium carbonate, and particularly preferred is sodium bicarbonate.

Can be used any solvent, because it has no effect on the reaction, including aromatic hydrocarbon solvents, esters of carboxylic acids, and ethers. Preferred are esters of carboxylic acids and ethers, and more preferred are the esters of carboxylic acids. The preferred aromatic hydrocarbon solvent is a toluene. Examples of esters of carboxylic acids include ethyl formate, methyl acetate, ethyl acetate, isopropylacetate and ethylpropane, with esters of acetic acid are preferred, and ethyl acetate is more preferred. Preferred ethers are ethers, cyclic ethers. Some simple examples of cyclic ethers include oxirane, tetrahydrofuran, tetrahydropyran and dioxane, and the tetrahydrofuran is preferred. The solvent used for karbonitrirovanija, preferably represents toluene, tetrahydrofuran or ethyl acetate, more preferably, tetrahydrofuran or ethyl acetate, and especially prepact the tion, the ethyl acetate.

The reaction temperature is usually in the range from approximately 0°to 120°C, preferably from 20°to 110°more preferably, from 40°C to 80°S, particularly preferably from 45°C to 70°C.

The reaction time is usually in the range of about 0.5 to 12 hours, preferably from 0.5 to 10 hours, more preferably from 0.5 to 3 hours. At this stage, chloroformiate, usually used in an amount of 5 to 15 equivalents, preferably from 7 to 13 equivalents, more preferably from 8 to 12 equivalents, particularly preferably, from 10 to 12 equivalents, relative to compound of formula (I).

At this stage, the base is generally used in an amount of 5 to 18 equivalents, preferably from 7 to 15 equivalents, more preferably from 9 to 12 equivalents, relative to compound of formula (I).

All urethane group compound 2 represented by the formula (III), remove from obtaining compound 3 represented by the formula (IV) (second stage). Removal of urethane groups is produced by standard reactions unprotect. Examples of such reactions unprotect include the catalytic hydrogenation and acid treatment. Preferred are catalytic hydrogenation in the presence of a catalyst of palladium on coal processing organizes the th acid, such as formic acid, acetic acid, propionic acid, oxalic acid or fumaric acid, and inorganic acid, such as hydrochloric acid or phosphoric acid. Especially preferred is a catalytic hydrogenation in the presence of a catalyst of palladium on coal. When the reaction unprotect used catalyst palladium on coal, the catalyst typically used in 0.01 to 1.0-fold amount, preferably 0.1 to 0.5 times the quantity, more preferably 0.13 to 0.39-fold amount, relative to the compound of formula (I)used in the first stage. The catalytic hydrogenation is preferably carried out in basic conditions. Examples of bases suitable for this purpose include inorganic bases such as sodium bicarbonate, potassium carbonate and sodium hydroxide, and tertiary amines such as triethylamine and diisopropylethylamine. Preferred are inorganic bases, more preferred are sodium bicarbonate and potassium carbonate, and particularly preferred is sodium bicarbonate.

As the source of hydrogen can be hydrogen, monitorial or something like that. When the source of hydrogen is hydrogen, catalytic HYDR who genitalia can be carried out under pressure, preferably, at a pressure of from about 0.01 to 1.0 MPa, more preferably from 0.05 to 0.5 MPa. Can be used any solvent, as it is inert to the reaction, preferably, incl. alcoholic solvents and ester solvents. More preferred solvents are methanol, ethanol and ethyl acetate, and particularly preferred is methanol. The reaction temperature is usually in the range from approximately 0°C to 60 °With, preferably, from 10°C to 50°more preferably, from 20°C to 40°C. the reaction Time is usually in the range of about 0.5 to 3 hours, preferably from 1 to 2 hours.

The nitrogen atom in the 3'-position desosamine ring in compound 3 represented by the formula (IV), alkylate with obtaining compound 4 represented by the formula (II) (the third stage). Examples of alkylating agent used for the alkylation at the third stage, include alkylhalogenide, alkylsulfate and alkylsilane, with alkylhalogenide are preferred. Preferred alkylhalogenide has the isopropyl group as its alkyl residue. Examples isopropylidene agent include isopropylated, isopropylbenzenesulfonyl and isopropyl-p-toluensulfonate, with isopropylated is preferred. Examples of the basis of the project, suitable for use include organic bases (e.g. amines and inorganic bases. Preferred are diisopropylethylamine, triethylamine, morpholine, piperidine, pyrrolidine and pyridine, and more preferred is triethylamine. Can be used any solvent, as it is inert to the reaction. Preferred are aprotic polar solvents and alcohol solvents, and more preferred are dimethylimidazolidine, dimethylformamide, acetonitrile, and the like. Alkylating agent, usually used in amounts of from 6 to 15 equivalents, preferably from 7 to 13 equivalents, more preferably from 8 to 12 equivalents, particularly preferably from 8 to 10 equivalents relative to the compound of formula (I)used in the first stage. The base is usually used in an amount of 5 to 15 equivalents, preferably from 7 to 13 equivalents, more preferably from 8 to 12 equivalents, relative to compound of formula (I). The solvent is generally used in 2-12-fold amount, preferably 3-10 times the amount, more preferably 3-8-fold amount, particularly preferably 3-6-fold amount, relative to the compound of formula (I)used in the first study is.

The reaction temperature is usually in the range from approximately 0°to 130°C, preferably from 50°to 100°more preferably, from 60°to 90°C. the reaction Time is usually in the range of about from 3 hours to 10 days, preferably from 5 to 10 hours.

Compound 4 represented by the formula (II)is converted to the fumaric salt, to obtain the fumaric salt compound 4 represented by the formula (II) (fourth stage).

The conversion of fumaric salt is carried out using standard methods for the formation of salts. Examples of solvents suitable for use include alcohol solvents, ether solvents, acetone and ethyl acetate, while alcohol solvents are preferred. Among them, preferred are methanol, ethanol and isopropanol, more preferred are methanol and isopropanol, and particularly preferred is isopropanol. These solvents may be used alone or in combination. When to convert fumaric salt is used fumaric acid, fumaric this acid is usually used in an amount of from 0.3 to 2 equivalents, preferably from 0.3 to 1 equivalent, more preferably from 0.4 to 0.8 equivalent, particularly preferably from 0.4 to 0.6 equivalent, with respect to the connection is of formula (II). The reaction temperature is usually in the range from about 20°to 100°C, preferably from 0°to 90°more preferably, from 20°C to 80°C. the reaction Time is usually in the range of about 1 to 6 hours, preferably from 3 to 4 hours.

Fumaric salt compound 4 represented by the formula (II), purify, getting cleaned fumaric salt of compound 4 (fifth stage).

Fumaric salt of the compounds of formula (II) is treated according to the need. Preferably, the purification is carried out by recrystallization. Examples of the solvent for recrystallization include ester solvents which may contain water, alcohol solvents, which may contain water, ether solvents, which may contain water, and mixtures of these solvents. Preferred is isopropanol mixed solvent of methanol/isopropanol and mixed solvent of ethyl acetate/water, and more preferred is isopropanol and mixed solvent of methanol/isopropanol. The ratio of methanol and isopropanol mixed solvent preferably ranges from 10:90 to 50:50, more preferably from 20:80 to 30:70. The ratio of ethyl acetate and water in the mixed solvent is preferably in the range from 99.5:0.5 to 95:5, more preferably from 99:1 to 96:4, especially p is edocfile, from to 98.5:1.5 to 97:3.

Preferably, the above phase recrystallization is carried out at lower temperatures. Usually it starts at a temperature of from 10°to 100°With, preferably, from 10°to 90°more preferably, from 20°C to 80°S, especially preferably from 70°C to 80°C. Typically, the temperature decreases at a rate from 5°/h to 130°C/h, preferably from 10°/h to 120°C/hour, more preferably, from 10°C/hour up to 50°C/h, particularly preferably from 10°C/hour up to 30°C/hour.

Typically, the temperature is reduced to a final temperature -10°0°C.

When cleaning is carried out recrystallization, it is preferably repeated twice or more. When the recrystallization is repeated twice or more, fumaric salt preferably precrystallizer from isopropanol and then from a mixed solvent of methanol/isopropanol.

EXAMPLES

The present invention is described below in the following examples, which are intended not to limit the scope of the present invention. In the following examples, data1H-NMR represent only the characteristic peaks. The degree of conversion and purity are determined by high performance liquid chromatography (HPLC).

Example 1: Synthesis of Z is connected to the I (Compound 6)

Ethyl acetate (63,1 kg) is added to compound 5 (dihydroxy compound; 14 kg) and sodium bicarbonate (11.3 kg). After that, the mixture is heated to 55°add benzyloxycarbonylamino (6.6 kg) and stirred for 1 hour. Add additional benzyloxycarbonylamino (29.5 kg) and stirred for 1 hour, followed by cooling. As a result, the original dihydroxy compound (Compound 5) and intermediate compound in the reaction (Compound 5, protected by one benzyloxycarbonyloxy group) completely disappear, and they are converted, each, specified in the header of the connection.

To this solution was added pyridine (0.015 kg) and stirred for 0.5 hour. This procedure, when added pyridine (0.015 kg) and stirred for 0.5 hours, repeat 3 more times, and then adding additional pyridine (5.3 kg).

To this solution was added water (70,0 kg) and stirred, with subsequent distribution to remove the aqueous phase. After that, the organic phase is washed with saturated salt solution (70,0 kg) and concentrated under reduced pressure, to obtain specified in the connection header in the form of oil.

Example 2: Synthesis nanometrology connection (Connection 7)

The compound prepared in example 1 is used without isolation and purification. This connection is of added methanol (88,5 kg), 10% palladium on coal (3.6 kg) and sodium bicarbonate (16,2 kg) and stirred in hydrogen atmosphere (0.1-0.4 MPa) for 1 hour at 25°S-50°C. as a result, the original Z connection (Connection 6) and intermediate compound in the reaction (Compound 6, where one benzyloxycarbonyl group is removed by removing protection) completely disappear, and they are converted, each, specified in the header connection. After palladium on coal filtered, the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate (88,4 kg), to which were then added saturated aqueous sodium bicarbonate solution (49,0 kg) and stirred, followed by distribution, removal of the aqueous phase. Then the organic phase is washed with saturated salt solution (49,0 kg), and concentrated under reduced pressure, to obtain specified in the connection header in the form of oil.

Example 3: Synthesis of isopropyl compounds (Compound 8)

The compound prepared in example 2 is used without isolation and purification. To this connection type 1,3-dimethyl-2-imidazolidinone (of 58.9 kg). To this solution add triethylamine (19,5 kg) and isopropyl iodide (29,4 kg)75°C, and stirred with heating for 6 hours to convert 98% of the original nanometrology connection (Connection 7) indicated the data in the header connection. After cooling to 30°With or below, add ethyl acetate (82,0 kg) and 25% aqueous solution of ammonia (3.6 kg). To this solution add additional water (70,0 kg) and stirred, followed by distribution, removal of the aqueous phase. This procedure, when water is added and stirred, followed by distribution, removal of the aqueous phase, repeated twice more. The organic phase is concentrated under reduced pressure, to obtain specified in the connection header.

Example 4: Synthesis AMO connection (fumaric salt of compound 8)

The compound prepared in example 3 is used without isolation and purification. This connection is added fumaric acid (1.1 kg) and isopropanol (109.9 kg) and heated to 71°followed by cooling to 10°or lower rate of 20°C/hour. Precipitiously crystals are collected by filtration, obtaining crystals specified in the connection header (wet powders; calculated yield of dry product: 86,2%; purity: 92,21%). To wet powders add isopropanol (to 106.0 kg) and heated to 71°followed by cooling to 10°or lower rate of 20°C/hour. Precipitiously crystals are collected by filtration, obtaining crystals specified in the connection header (wet powder; purity: a total of 8.74%).

Example 5: Purification of AMO connection (fumaric salt of compound 8)

The crystals prepared in example 4 is used without drying. The crystals add methanol (2.5 volume calculated on the dry mass of the compound prepared in example 4) and isopropanol (7.5 volumes calculated on the dry mass of the compound prepared in example 4), and heated to 60°followed by cooling to 0°or lower rate of 20°C/hour. Precipitiously crystals are collected by filtration, to obtain crystals (wet powder) specified in the connection header. The above procedure is repeated again, without drying the obtained crystals, get crystals specified in the connection header (wet powder; purity: 99.44%).

Example 6: Synthesis of Z compounds (Compound 10)

Ethyl acetate (225 ml) is added to Compound 9 (dihydroxy compound; 45,0 g, 63.1 mmol) and sodium bicarbonate (37,1 g, 441,6 mmol). After heating the mixture to 55°add benzyloxycarbonyl chloride (21,5 g, 126,2 mmol), and stirred for 1 hour. As a result, the original dihydroxy compound (Compound 9) and intermediate compound in the reaction (Compound 9, secured one benzyloxycarbonyloxy group) completely disappear, and they are converted, each, specified in the header connection. Add an additional number is on benzyloxycarbonyl chloride (96,9 g, 567,7 mmol), and stirred for 1 hour, followed by cooling.

To this reaction mixture are added water (300 ml) and stirred, followed by distribution, removal of the aqueous phase. This procedure, when adding water (300 ml) and stirred, followed by distribution, removal of the aqueous phase, repeat twice. After that, the organic phase is washed with saturated salt solution (200 ml) and concentrated under reduced pressure, to obtain specified in the connection header (140,3 g) in the form of oil.

Connection 10 Example 7: Synthesis nanometrology compound (Compound 11)

The compound prepared in example 6, is used without isolation and purification. To this compound (20.4 g, 28.6 mmol) is added methanol (102 ml), 10% palladium on coal (5.3g) and sodium bicarbonate (24,0 g, 285,7 mmol), and stirred in hydrogen atmosphere (0.1-0.4 MPa) for 1 hour at 25°S-50°C. as a result, the original Z compound (Compound 10) and intermediate compound in the reaction (Compound 10, where one benzyloxycarbonyl group is removed by removing protection) completely disappear, and they converted each, specified in the header connection. After palladium on coal is filtered off, the filtrate is concentrated under reduced pressure. The remainder of the process is Aut in ethyl acetate (300 ml), to which you then add water (200 ml) and stirred, followed by distribution, removal of the aqueous phase. To this solution add additional water (200 ml) and stirred, followed by distribution, removal of the aqueous phase. Similarly, the organic phase is then washed with a saturated salt solution (200 ml) and concentrated under reduced pressure, to obtain specified in the connection header (26,3 g) in the form of oil.

Example 8: Synthesis of isopropyl compound (Compound 12)

Connection (21,6 g, 30,8 mmol)prepared in example 7, is used without isolation and purification. To this connection type 1,3-dimethyl-2-imidazolidinone (86 ml). To this solution add triethylamine (31.1 g, 307,5 mmol) and isopropylated (47,0 g, 276,8 mmol)at 75°C, and stirred with heating for 6 hours to convert 98% of the original nanometrology compound (Compound 11) specified in the header connection. After cooling to 30°With or below, add ethyl acetate (500 ml) and 25% aqueous solution of ammonia (5,4 ml). To this solution add additional water (300 ml) and stirred, followed by distribution, removal of the aqueous phase. This procedure, when additional water is added (300 ml) and stirred, followed by distribution, removal of the aqueous phase, repeat 3 RA is and. The organic phase is concentrated under reduced pressure, to obtain specified in the title compound (22.1 g).

Example 9: Synthesis AMO connection (fumaric salt compound 12)

The compound prepared in example 8, is used without isolation and purification. To this compound (17.0 g, is 22.9 mmol) is added fumaric acid (1.3 g) and isopropanol (170 ml) and heated to 71°followed by cooling to 10°C or below, with a speed of 20°C/hour. Precipitiously crystals are collected by filtration, to obtain crystals (6.8 g) AMO connection (fumaric salt compound 12).

Example 10: Cleaning AMO connection (fumaric salt compound 12)

The crystals prepared in example 9, are used without drying. To the crystals (6,59 g) is added methanol (8.2 ml) and isopropanol (24,8 ml) and heated to 60°followed by cooling to 0°C or below, with a speed of 20°C/hour. Precipitiously crystals are collected by filtration, to obtain crystals (4.83 g; purity: 98,77%) AIA connection (fumaric salt compound 12).

1H-NMR (Dl3, ppm):

4,9-5,0 (1H, DD), 4,8 (1H, d), 4,4 (1H, DD), 3,9-4,1 (2H, m), 3,8-3,9 (2H, m), 3,5 (1H, m), and 3.3 (3H, s), 3,1-3,2 (1H, m), 2,9-3,1 (2H, m), 2,3-2,8 (6N, m)2,2 (3H, s), of 1.5-2.1 (8H, m), 1.0 to 1,5 (34N, m), and 0.9 (3H, t).

Example 11. Synthesis of Z connection

THF (15 ml) is added to compound 5 (hydro shall cicadinea, 3 g) and sodium bicarbonate (5,2 g). After that, the mixture is heated to 30°add benzyloxycarbonylamino (6.3 g) and stirred for 1 hour and then cooled. To the resulting solution was added pyridine (1.0 g) and stirred for 2 hours.

To this reaction mixture are added ethyl acetate (30 ml) and a saturated solution of salt. The organic phase is washed with saturated salt solution (20 ml) and concentrate under reduced pressure to obtain specified in the title compound as oil (11,0 g).

Industrial application

The way of getting the present invention is industrially advantageous because (1) ensuring high efficiency of the reaction and a reduced reaction time, (2) providing a considerable simplification of the method and reduce the time and effort required for this method to resolve such procedures as changing the solvent, (3) decrease the risk of decomposition of the product during the reaction, (4) lower content of residual solvent, because the resulting reaction product is easy to dry, (5) to obtain compounds of high quality and high purity, and the like. Thus, the method of receiving according to the present invention is suitable for use in industrial applications.

1. The method of obtaining the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES with obtaining the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group, methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or a urethane group as defined above);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV)

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3’-position disseminator number is CA, in the compound of formula (IV), to obtain the compounds of formula (II); and

the conversion of compounds of formula (II) fumaric salt;

where the compound of formula (I) interacts with CHLOROFORMATES in the presence of simple cyclic ether or ether carboxylic acid, to obtain the compounds of formula (III).

2. The method of obtaining the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group selected from methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyl the school group, and R4represents a hydrogen atom or a urethane group as defined above);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV)

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3’-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II); and

the conversion of compounds of formula (II), fumaric salt;

where urethane groups of the compounds of formula (III) is removed in the presence of sodium bicarbonate to obtain the compounds of formula (IV).

3. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III)

(where R1represents a hydrogen atom or Nissho the alkyl group, R3represents a urethane group, selected methyloxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or urethane group);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV)

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3’-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II);

the conversion of compounds of formula (II), fumaric salt, to obtain the fumaric salt compounds; and

crystallization fumaric salt from a solvent containing alcohol;

where crystalline form is obtained by crystallization from isopropanol.

4. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II):

(where R1represents a hydrogen atom or a lower alkyl GRU is PU, and R2represents a lower alkyl group), which includes

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group selected from methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or a urethane group as defined above);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV)

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3’-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II);

the conversion of compounds of formula (I), in fumaric salt, to obtain the fumaric salt compounds;

crystallization fumaric salt from a solvent containing alcohol, to obtain the crystalline form; and

the recrystallization of the crystals from the solvent containing alcohol;

where the crystals precrystallization from isopropanol.

5. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with CHLOROFORMATES, obtaining the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group selected from methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole Inoi group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or a urethane group as defined above);

remove all urethane groups of the compounds of formula (III), to obtain the compounds of formula (IV)

(where R1represents a hydrogen atom or a lower alkyl group);

alkylation of the nitrogen atom in the 3’-position desosamine ring in the compound of formula (IV), to obtain the compounds of formula (II);

the conversion of compounds of formula (II), fumaric salt, to obtain the fumaric salt compounds;

crystallization fumaric salt from a solvent containing alcohol, to obtain the crystalline form; and

the recrystallization of the crystals from the solvent containing alcohol;

where the crystals precrystallization from isopropanol and then from a mixed solvent of methanol/isopropanol.

6. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes

the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with chloroformate, in the presence of simple cyclic ether or ether carboxylic acid, to obtain the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group selected from methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or a urethane group as defined above);

remove all urethane groups of the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group as defined above and R4represents a hydrogen atom or urethane group), in the presence of sodium bicarbonate, to obtain the compounds of formula (IV)

(where R1is an atom ogorodili lower alkyl group);

crystallization fumaric salts of the compounds of formula (II), from isopropanol, to obtain the crystalline form of the fumaric salt compounds; and

the recrystallization of the crystals from isopropanol and then from a mixed solvent of methanol/isopropanol.

7. The method of obtaining the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group selected from methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or urethane group), which includes the interaction of the compounds of formula (I)

(where R1represents a hydrogen atom or a lower alkyl group) with chloroformate, in the presence of simple cyclic ether or ether carboxylic acid.

8. The method of obtaining the compounds of formula (IV)

(where R1represents a hydrogen atom or issue alkyl group), which involves removing all urethane groups of the compounds of formula (III)

(where R1represents a hydrogen atom or a lower alkyl group, R3represents a urethane group selected from methoxycarbonyl group, ethoxycarbonyl group, 2-feniltiosemicarbazonele group, tert-butyloxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group, p-methoxybenzylideneamino group, p-nitrobenzisoxazole group, benzyloxycarbonyloxy group, and R4represents a hydrogen atom or a urethane group, defined above)in the presence of sodium bicarbonate.

9. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the crystallization of fumaric salts of the compounds of formula (II), of isopropanol.

10. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl the second group, and R2represents a lower alkyl group), which includes the recrystallization of the crystals fumaric salts of the compounds of formula (II), of isopropanol.

11. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the recrystallization of the crystals fumaric salts of the compounds of formula (II), from isopropanol and then from a mixed solvent of methanol/isopropanol.

12. A method of obtaining a crystalline form of the fumaric salts erythromycin derivative of the formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), which includes the crystallization of fumaric salts of the compounds of formula (II), from isopropanol, to obtain the crystalline form of the fumaric salt compounds, and the recrystallization of the crystals from isopropanol and then from a mixed solvent of methanol/isopropanol.

13. The method according to claim 1 or 6, where the interaction with chloroformiate carried out in the presence of an ether carboxylic acid.

14. The method according to claim 1, where the ether carboxylic acid is an ester of acetic acid.

15. The method according to item 13, where the ether carboxylic acid is an acid ethyl ester.

16. The method according to one of claims 1 to 6, where fumaric salt of the compounds of formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), crystallizes at lower temperatures.

17. The method according to clause 16, where the temperature decreases with the speed from 10 to 120°C/hour.

18. The method according to any one of claims 1 to 6 and 16-17, where the crystalline form of fumaric salts of the compounds of formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), precrystallizer with decreasing temperature.

19. The method according to p, where the temperature decreases with the speed from 10 to 120°C/hour.

20. The method according to claim 9, where the fumaric salt of the compounds of formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), crystallizes at lower temperatures.

21. The method according to claim 20, where the temperature decreases with the speed of the t 10 to 120° C/hour.

22. The method according to item 12, where the fumaric salt of the compounds of formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), crystallizes at lower temperatures.

23. The method according to item 22, where the temperature decreases with the speed from 10 to 120°C/hour.

24. The method according to any of p-12 and 22-23, where the crystalline form of fumaric salts of the compounds of formula (II)

(where R1represents a hydrogen atom or a lower alkyl group, and R2represents a lower alkyl group), precrystallizer with decreasing temperature.

25. The method according to paragraph 24, where the temperature decreases with the speed from 10 to 120°C/hour.

26. The method according to any one of claims 1 to 6 and 13 to 19, where R3and/or R4are benzyloxycarbonyloxy group.

27. The method according to any one of claims 1 to 26, where R1represents a methyl group.

28. The method according to any one of claims 1 to 6 and 9-26, where R1represents a methyl group, and R2represents an ISO-propyl group.



 

Same patents:

The invention relates to 3’-Destinationin-9 oxyimino macrolides of formula (I):

in which R represents hydrogen or methyl; R1and R2both represent hydrogen or together form a chemical bond; R3represents hydrogen or linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated and contains from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups, X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group; r is an integer from 1 to 6; m is an integer from 1 to 8; n is an integer from 0 to 2; and their pharmaceutically acceptable salts; except for compounds of the oxime of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-descimated the

The invention relates to organic chemistry, in particular to methods of producing the compounds of formula (I):

in which m denotes 0, 1 or 2; n is 0, 1, 2 or 3 and a represents a double bond, represents a double or a simple link, With denotes a double bond, D represents a simple bond, E and F represent a double bond; r1denotes N or C1-C8alkyl; r2denotes H, C1-C8alkyl or HE; R3and R4each independently of one another denote H or C1-C8alkyl; R5denotes N or C1-C8alkyl; R6denotes H; R7IT denotes; R8and R9independently of one another denote H or C1-C10alkyl; in free form or in salt form, which consists in the fact that the compound of formula (II):

enter in contact with the biocatalyst, which is able to selectively oxidize the alcohol in position 4", obtaining the compounds of formula (III):

in which R1-R7, m, n, a, b, C, D, E and F have the same meaning as Kazakistan an amine of the formula HN(R8R9in which R8and R9have the same meaning as indicated for formula (I), with subsequent isolation of the target product in free form or in salt form

The invention relates to medicine, in particular to Oncology, and for the treatment of cancer in a mammal

The invention relates to a process for the preparation of clarithromycin in the form of crystals of form II, as well as to new intermediate compounds used in the specified way

The invention relates to a process for the preparation of clarithromycin of formula (I), including the interaction of the N-oxide erythromycin And formula (II) with meteorous agent with obtaining N-oxide 6-O-methyl-erythromycin a of formula (III) and processing of N-oxide-6-O-methylerythromycin And reducing agent

The invention relates to 12,13-dihydroxypropane tylosin General formula I, where R, R1CHO, CH=NOH, CH(OCH3)2; R2- H, mikrosil; R3- N(CH3)2NO(CH3)2;- double or a simple link, a new semisynthetic compounds of the macrolide class and method of production thereof

The invention relates to a derivative of (2R, 3S, 4S, 5R, 6R, 10R,11R)-2,4,6,8,10-pentamethyl-11-acetyl-12,13-dioxabicyclo[8.2.1] tridec-8-EN-1-it General formula (I), where R1denotes hydrogen or methyl and R2denotes hydrogen or (NISS
The invention relates to the field of medicine

The invention relates to compounds represented by the General formula (I)

< / BR>
where A represents NH group, and thus C=O-group or A - C=O-group and thus NH-group, R1HE band, L-clavesilla group of the formula (II)

< / BR>
or together with R2is a ketone; R2is hydrogen or together with R1represents a ketone; R3is hydrogen or C1-C4-alcoolica group, and pharmaceutically acceptable salts of the accession of organic and inorganic acids

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.

EFFECT: improved preparing and purifying method.

28 cl, 11 ex

FIELD: production of macrolide road-spectrum antibiotic tylosine.

SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.

EFFECT: method for production of tylosine base in granulated form with homogeneous composition.

2 cl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.

EFFECT: improved method for preparing.

3 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to a novel crystalline form E of erythromycin derivative fumarate salt represented by the formula (I)

and to a method for its preparing. Indicated crystalline form E shows strong roentgen diffraction peaks at diffraction angles (2θ) 5.6° and 10.4° that was established by roentgen diffractometry with Cu-Kα-radiation. Also, invention proposes crystalline form D of erythromycin derivative fumarate salt represented by the formula (I) showing average particles size 90 mcm or above and/or the content of residual solvent 1500 ppm or less. Method for preparing indicated crystalline form D involve suspending indicated crystalline form E in mixture ethyl acetate and water in the ratio = (99:1)-(97:3) at temperature from -20°C to 20°C. Invention provides reducing the content of residual solvent and elimination of difficulties in making tablets.

EFFECT: improved preparing methods.

14 cl, 1 tbl, 5 dwg, 6 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.

EFFECT: improved preparing methods.

16 cl, 8 dwg, 13 ex

FIELD: antibiotics.

SUBSTANCE: invention relates to azithromycin as a stable monohydrate comprising from 4.0% to 6.5% of water and to a method for its preparing. Invention provides preparing the stable form of azithromycin monohydrate.

EFFECT: improved preparing method.

3 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention concerns macrolide compounds of the formula I , where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: , where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 and R2 together form a link; R3 is a hydroxygroup or forms a =N-O-R5 group together with R4, where R5 is hydrogen, alkyl or a chain of the formula -(CH2)r-X-(CH2)m-Y-(CH2)n-A where r, m, n are the whole number as defined above; A is hydrogen, thiazolyl, furanyl or thiophenyl; X is NR6 where R6 is hydrogen; Y is a phenylene group or NR6 where R6 is hydrogen; R4 is hydrogen or forms =N-O-R5 group together with R3, with the same R5 as defined above; and its pharmaceutically acceptable salts, on the condition that R1 is not a dimethylamino group when R3 is a hydroxy group, and both R2 and R4 are hydrogen; R1 is not a dimethylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl; R1 is not a methylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl. The invention also concerns a method of obtaining the claimed compounds by elimination of L-cladinose residuum in the 3 position in compounds of the general formula II , where R, R1, R2, R3 and R4 are the same as defined above. Besides, the invention also concerns compounds of the general formula II, where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1- C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen or C1-C3alkoxycarbonyl; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen or C1- C3alkoxycarbonyl; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 forms a link together with R2; R3 is a hydroxy group; R4 is hydrogen; and their pharmaceutically acceptable salts; on the condition that (i) R1 is not N,N-dimethylamino or (ii) R1 is not N,N-dimethylamino-N-oxide when R is hydrogen. The invention also concerns pharmaceutical composition based on the compound of the formula I, exhibiting anti-inflammatory effect.

EFFECT: obtaining of compounds with anti-inflammatory effect.

29 cl, 78 ex

FIELD: chemistry.

SUBSTANCE: invention concerns avermectin B1 and avermectin B1 monosaccharide derivatives of the general formula I , where n is 0 or 1; A- B is -CH=CH- or -CH2-CH2-; R1 is C1-C8-alkyl, C3-C8-cycloalkyl or C2-C8-alkenyl; R2 is C1-C8-alkyl or C2-C8-alkenyl, optionally substituted by a subsitutde selected out of the group of -OH, - N3, -NO2, C1-C8-alkoxy-, C1-C6-alkoxy-C1-C6-alkoxy, C1-C8-alkylthio, C1-C8-alkylsulfinyl, C1-C8-alkylsulfonyl, -NR4R6, -X- C(=Y)-R4, -X-C(=Y)-Z-R4, or phenyl substituted optionally by halogen; R3 is H or C1-C8-alkyl substituted by halogen; or R2 and R3 together are a 3-7-membered alkylene bridge substituted optionally by C1-C4-alkyl, or form together a -CH2-CH2-O-CH2- or -CH2-CH2-C(=O)-CH2- group; X is -O- or NR5; Y is -O-; Z is -O-; R4 is hydrogen or C1-C8-alkyl substituted optionally by C1-C6-alkoxy; R5 is hydrogen or C1-C8-alkyl; R6 is hydrogen or C1-8-alkyl if the compound is not a avermectin B1a or B1b derivative where n is 1, R3 is H and R2 is -CH2-CH2-OCH3 or -CH2-CH2-O-phenyl; and is not a B1a or B1b derivative where n is 1, and R2 and R3 form together an unsubstituted -CH2-CH2-CH2- group; while their E/Z isomers, mixes of E/Z isomers and/or tautomers, in a free or salt form in each case.

EFFECT: production of insecticide composition and method of cultivated plant pest eradication.

7 cl, 5 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention concerns (a) new compounds of the formula I: , where M is a macrolipid subunit (macrolipid group) obtained from a macrolipid inclined to accumulation in inflamed cells, S is a steroid subunit (steroid group) obtained from a steroid medicine with anti-inflammatory effect, and L is a linker molecule connecting M and S; (b) their pharmacologically acceptable salts, prodrugs and solvates; (c) methods and mediators for their obtaining; and (d) methods of their application in treatment of human and animal inflammation diseases and conditions. The claimed compounds are inhibiting many cytokines and immune mediators participating in immune reactions that cause inflammation, allergy or alloimmunity, including IL (interleukin)-1, 2, 4, 5, 6, 10, 12, GMCSF (Granulocyte Macrophage Colony Stimulating Factor), ICAM (Intercellular Adhesion Molecule) and TNF (tumour necrosis factor) - α without limitation. At that, antiinflammation steroids have immediate anti-inflammatory effect due to the link to glycocorticosteroid receptor.

EFFECT: application in treatment of human and animal inflammation diseases and conditions.

30 cl, 40 ex, 4 dwg

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