Method for preparing erythromycin oxime

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

 

The invention relates to the production of medical preparations, namely, to obtain a chemical derived natural antibiotic erythromycin A (I) - oxime erythromycin (II). The oxime of erythromycin is used for synthesis of various semi-synthetic eritromicina, of which the most famous azithromycin roxithromycin and clarithromycin.

Known methods for producing oxime erythromycin maximilianeum erythromycin 3-5-fold excess of hydroxylamine or its salts in an environment of lower alcohols or water-alcohol solutions at a temperature of 50°-80°With neutral or slightly acidic pH values. To create the necessary acid-alkaline environment in the reaction mass is added the acid, if maximilianii spend with base aqueous solution of hydroxylamine (U.S. patent No. 5,808,017) or an aqueous solution of a base, if maximiliane use hydroxylamine hydrochloric acid with strong acid properties (patent RF №2144924, RF patent №2199546). The disadvantage of these methods is to conduct the reaction in an aqueous-organic medium due to the use of aqueous solutions of hydroxylamine or base which when heated causes the hydrolysis erythronolide ring eritromicina, reducing output and accumulation in the reaction mass products destru the tion eritromicina.

Closest to the claimed method, the means of obtaining the oxime of erythromycin in dry methanol using hydroxylamine hydrochloric acid and dry Foundation to create the desired acid-alkaline environment. As grounds can be used barium carbonate (patent of great Britain No. 1,100,504) or sodium carbonate (patent USSR No. 1447288). The disadvantage of these methods is that the used of the base is not soluble in alcohols, so the reaction proceeds slowly in heterogeneous conditions and is required to complete the extract at a temperature of 50°-80°10-20 hours, which leads to thermal degradation eritromicina, in addition, the exchange reactions between carbonates and hydroxylamine hydrochloric acid is excreted carbon dioxide and water, so the reaction mass is quenched, which promotes the hydrolysis eritromicina.

The aim of the invention is to increase the output and quality of the oxime of erythromycin by carrying out the reaction in non-aqueous environment and homogeneous conditions, which as the basis of use-soluble organic solvent triethylamine, which when interacting with hydroxylamine hydrochloric acid, unlike carbonates, does not lead to release of water.

Maximilianii as follows: a mixture of er is Tropicana with three to five-fold excess of hydroxylamine hydrochloric acid and two or threefold excess of triethylamine in dry methanol are heated to a temperature of 50° -80°With, this forms a transparent homogeneous solution, and incubated for 4-6 hours, obtained in this way, the oxime of erythromycin can be isolated from the reaction mass in the form of a hydrochloride by cooling the mixture and form the Foundation upon dilution of the reaction mixture with water and alkalization to pH 8-10 or used in the form of a solution.

Example 1.

Obtain the hydrochloride of the oxime of erythromycin.

In trevorrow flask with reflux condenser load 180 ml of methanol, pour 38 ml of triethylamine, sprinkle 41.5 g of hydroxylamine hydrochloric acid, stir for 10 minutes, sprinkle 100 g of erythromycin, heated to a temperature of 70°and stir for 5 hours. The reaction mass to cool, to stand for 6 hours, the precipitation of the hydrochloride of the oxime of erythromycin filter, the paste is washed with 400 ml of hexane, dried at a temperature of 40°C for 6 hours. The weight of the dry powder 105, Chromatographic purity (HPLC) of the hydrochloride of the oxime of erythromycin 87%. Melting point 187-192°C. Yield 85%, counting on erythromycin A.

Example 2.

Getting the base of the oxime of erythromycin.

In trevorrow flask with reflux condenser load 200 ml of methanol, pour 42 ml of triethylamine, sprinkle with 45.5 g of hydroxylamine hydrochloric acid, stir for 10 minutes, sprinkle 100 g of erythromycin heated to a temperature of 50° C and stir for 6 hours. The reaction mass is poured in a thin stream with vigorous stirring in 1000 ml of 5% sodium carbonate solution, heated to 50°stir for 30 minutes, if necessary, adjust the pH to 8-10, the suspension is filtered, the paste is washed with 500 ml of water, heated to 50°C, dried in a vacuum drying Cabinet. The weight of the dry powder 92 g, chromatographic purity of the oxime of erythromycin 94%. Melting point 184-189°C (decomposition). Output to 84.6%, counting on erythromycin A.

Example 3.

Getting chloridometer solution of the oxime of erythromycin. In trevorrow flask with reflux condenser load 180 ml of methanol, pour 33 ml of triethylamine, sprinkle of 30.6 g of hydroxylamine hydrochloric acid, stir for 10 minutes, sprinkle 100 g of erythromycin, heated to a temperature of 70°and stir for 6 hours. The reaction mass to cool, pour it 1000 ml of water and 1000 ml of methylene chloride, to podselect emulsion 10% solution of sodium hydroxide until a pH of 9.0, the organic layer containing the oxime of erythromycin separated, washed with 250 ml of water at a pH value of 7.0. To the washed chlorothalidone solution to cover 75 g anhydrous sodium sulfate, stir for 4 hours, to filter, sodium sulfate wash 200 ml of methylene chloride, washing attach to the OS the ESD solution. Volume chloridometer solution 1180 ml, the content of the oxime of erythromycin 74 mg/ml

The method of producing oxime erythromycin maximilianeum erythromycin hydroxylamine hydrochloric acid in methanol, characterized in that maximilianii are using as the basis of triethylamine.



 

Same patents:

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: 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: 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

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

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

Up!