The way to get azithromycin dihydrochloride
(57) Abstract:The invention relates to a new process for the preparation of the dihydrochloride of azithromycin, which is a pharmaceutically acceptable salt of the antibiotic azithromycin, suitable as an antibacterial agent with a broad spectrum of action. Describes how to obtain azithromycin dihydrochloride, wherein interact monohydrate azithromycin or dihydrate azithromycin dissolved in low (C1- C4) alcohol or low (C3- C6) ketone, 1.6 to 2 equivalents of hydrochloric gas dissolved in dry low (C1- C4) alcohol at a concentration of 12 - 20% (wt/V) and at a temperature of from 10 to 15oC, the resulting product is then precipitated by the precipitator at a temperature of from 10 to 25oC, when the ratio of solvent to the precipitator from 1 : 1.8 to 1 : 8 (V/V) and then allocate filtering. The technical result - the creation of a more acceptable from an economic and technical perspective a new way. 1 C.p. f-crystals. The invention relates to a new process for the preparation of the dihydrochloride of azithromycin, which is a pharmaceutically acceptable salt of the antibiotic azithromycin, suitable cachesettings, semi-synthetic antibiotic, the representative of the class of azalides /Kobrehel G. et al, BE 892357, 7/1982; Bright, G. M., US 4474768, 10/1984 /has a broad spectrum of activity against bacteria, including gram-negative bacteria and intracellular microorganisms. Its hydrated form /SumamedR/ use in medicinal preparations suitable for oral administration, for the treatment of infectious bacterial diseases.The same biological properties known for its salt accession, dichloropurine of azithromycin, which, thanks to its good solubility in water, can be used for oral administration in pharmaceutically acceptable forms /injection, infusion/.So far in the literature have described two ways to get azithromycin dihydrochloride. According to Bright /the aforementioned patent /USA/ response interaction between azithromycin and pyridinecarboxamide carried out in methylene chloride, and after evaporation of the solvent from the aqueous solution by lyophilization allocate azithromycin dihydrochloride, while its output is 54%.According Djokic et al., J: chem. Resarch (M), (M), 1988, 1239 - 1,261 azithromycin dihydrochloride is obtained by lyophilization cleaners containing hydrochloride aqueous solution of azithromycin that azithromycin dihydrochloride can be obtained in a new deposition method, which is more acceptable from an economic and technical point of view, than the ways deducted in the literature so far.It was found that the azithromycin dihydrochloride can be obtained by a reaction between a mono - or dihydrate azithromycin dissolved in lowest /C1-C4/ alcohols or lower /C3-C6/ ketones with 2 equivalents of hydrochloric gas dissolved in dry low /C1-C4/ alcohol at a concentration of 12 - 20% /wt/rpm and a temperature of 10-15oC, whereupon the product precipitated by adding to the reaction mixture precipitator or by pouring the reaction mixture into the precipitator at a temperature of 10 - 25oC.The term "lower alcohols" here refers to alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol, and their isomeric forms.The term "lower ketones indicated ketones such as diethylketone, methyl ethyl ketone, isobutylmethylxanthine or similar compounds, in which the soluble mono - and dihydrate azithromycin, and which are also mixed with the precipitating product, for example, ethers, preferably diisopropyl ether.The ratio of solvent to the precipitator can izm added dropwise reactant of the reaction the suspension is stirred for one hour at the same temperature interval, then the received azithromycin dihydrochloride is filtered, washed precipitator and dried in vacuum.The way to get azithromycin dihydrochloride of the present invention is illustrated but in no way limited to the following examples.Example 1
To a solution dihydrate azithromycin /5 g, 0,0064 mol/ isopropanol /20 ml/ added dropwise under stirring for 5 minutes at a temperature of 10 - 15oC 2.5 ml of 18% hydrochloric gas in dry isopropanol /0,0124 mole of hydrochloric gas. The reaction mixture is added dropwise with stirring during 30 minutes to a diisopropyl ether /130 ml/. Stirring of the reaction mixture is continued for a further one hour at room temperature, then the precipitate was filtered, washed with cold isopropanol /5 ml and were dried for 5 hours in a vacuum dryer at 40oC. Received 5,15 g /98,4%/ azithromycin dihydrochloride, melting point : 186 - 192oC.1H NMR /CD3OD/ ppm /ppm/
2,84 /S, 9H N/ CH3/2and NCH3/
3,36 /S3H, OCH3/.Analysis of C38H72O12N22HCl
Calculated: 8,63 Cl
Found: 8,40% Cl
within 5 minutes at a temperature of 10-15oC 2.5 ml of 18% hydrochloric gas in dry isopropanol /0,0124 mole of hydrochloric gas. Then, while maintaining the same temperature in the reaction mixture for 1 hour was added dropwise diisopropyl ether /60 ml/. After stirring for 1 hour at the same temperature, the precipitated salt was filtered. Received 5.2 g /98,9%/ azithromycin dihydrochloride.Example 3
In accordance with the method described in example 2 of the dihydrate azithromycin /2 g 0,0025 moles/ dissolved in acetone /4 ml/ by reaction of interaction of 1.15 ml of 12.9% hydrochloric gas in dry methanol /0,0041 mole of hydrochloric gas/ got to 2.06 g /98,5%/ azithromycin dihydrochloride.Example 4
In accordance with the method described in example 1 of the monohydrate azithromycin /2G, 0,0026 moles/ dissolved in methanol /8 ml/, of 1.16 ml of 12.9% hydrochloric gas in dry methanol /0,0041 mole of hydrochloric gas/ and diisopropyl ether /16 ml/ received 2,10 g /98,5%/ azithromycin dihydrochloride. 1. The way to get azithromycin dihydrochloride, wherein interact monohydrate azithromycin or dihydrate azithromycin, rastvorennogo gas, dissolved in dry low (C1-C4) alcohol at a concentration of 12 - 20% (wt./about.) and at a temperature of from 10 to 15oC, the resulting product is then precipitated by the precipitator at a temperature of from 10 to 25oC, when the ratio of solvent to the precipitator from 1 : 1.8 to 1 : 8 (vol./about.) and then allocate filtering.2. The method according to p. 1, wherein the precipitant is a simple ether, particularly diethyl ether or diisopropyl ether.
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.
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
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
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
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
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