The method of obtaining clarithromycin in the form of crystals of form ii

 

Clarithromycin in the form of crystals of form II (formula I) are obtained by treatment of clarithromycin methanesulfonic acid in the mixture is miscible with water, an organic solvent and water with the formation of crystalline three-hydrate nelfinavir clarithromycin of formula (II), which is subjected to neutralization with an aqueous solution of ammonia in the mixture is miscible with water, an organic solvent and water. Clarithromycin with no pharmaceutical purity, obtained by protection of the 9-oximes hydroxy-group 9-oxime erythromycin a or its salt trepiline group, and 2’- and 4’-hydroxyl groups - trimethylsilyl groups with 9-About-tropological 2’,4’-O-bis(trimethylsilyl)erythromycin a, which is subjected to interaction with meteorous agent with obtaining 9-About-tropological 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And formulas, and then remove the protective group and oximo group. The invention relates to intermediate compounds of the formula (II) and formula (III), where1represents hydrogen or methyl, and R2represents hydrogen or trimethylsilyl, and if R1represents methyl, R2represents trimel., 4 Il.

The technical field,

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 method.

The level of technology

Clarithromycin, 6-O-methylerythromycin And is a semi-synthetic macrolide antibiotic of formula (I), which exhibits strong antibacterial activity against a broad spectrum of bacteria, including gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, chlamydia and Helicobacter pylori; and due to its high stability in the acidic environment of the stomach it can be administered orally for the treatment of many infectious diseases, and to prevent recurrence of ulcer disease when used in combination with other medicines

It was reported that clarithromycin exists, at least in three different crystalline forms, “form”, “form I” and “form II” (published international application WO 98/04573 and WO 98/alnoy scanning calorimetry and powder diffraction spectroscopy x-ray. Form II, which is thermodynamically more stable than form I, is used in medicines currently available on the market.

It was reported about the different ways of obtaining clarithromycin, for example, in patents EP 0147062, EP 0158467, EP 195960 and EP 260938, and in U.S. patent 4990602, 5837829, 5929219, 5892008, 5864023 and 5852180. In accordance with the most widely used methods, which are described further, as the intermediate use 9-axispointe erythromycin A.

Method 1), described in the patent EP 0158467, includes the following stages: protection oximes hydroxy-group, and 2’-hydroxy-group and 3’-dimethylaminopropyl 9-oxime erythromycin And benzyl group and benzyloxycarbonyl groups, respectively; methylation of 6-hydroxy-group; and removing the protective groups and the oxime group transformation of obtaining clarithromycin. However, this method requires the use of excessive amounts of caustic and toxic benzyloxycarbonylamino and unsuitable for commercial use because of the need for stages hydrogenolysis, which are difficult to implement on an industrial scale.

Method 2) described in the patent EP 0195960, includes the following stages: protection oximes hydroxyl what-hydroxy-group; and removal of protective groups and oxime group transformation of obtaining clarithromycin. However, this method is complicated by problems arising from the removal of the protective group.

Method 3), described in the patent EP 0260938, includes the following stages: protection oximes hydroxy-group 9-oxime erythromycin And benzyl or substituted benzyl group; protection 2'and 4’-hydroxy groups silyl groups, methylation of 6-hydroxy-group; and removing the protective groups and the oxime group transformation of obtaining clarithromycin. However, in accordance with this method of protection oxomnik groups is also removed by carrying out the hydrogenolysis reaction, which is unsuitable for large-scale production.

Next, method 4), described in U.S. patent 5837829, includes the following stages: protection oximes hydroxy-group, and 2'and 4’-hydroxyl groups of 9-oxime erythromycin And silyl groups; methylation of 6-hydroxy-group; and removing the protective groups and the oxime group transformation of obtaining clarithromycin. However, this method requires a stage of methylation in extremely arid conditions due to instability 9-oxysilanes groups in relation to water and difficult security when working with sodium hydride.

Thus, the known prior art methods of 1)-5) has some problems that must be solved in order to develop an improved method of receiving clarithromycin. In addition, the product - clarithromycin obtained by these methods above, is not clarithromycin pharmaceutical purity, which must be a pure crystalline form II of clarithromycin and represents clarithromycin, which has no need for pharmaceutical use quality in terms of purity and crystallinity. Accordingly, additional cleaning stage and special stage of crystallization for the conversion of clarithromycin, which has no need for pharmaceutical use, quality, pure Clary the preparations.

It was reported several methods of obtaining crystals of form II of clarithromycin, who had no need for pharmaceutical use quality. For example, crystals of the form 0 or I is heated in vacuum at a temperature of from 70 to 110With over a long period of time with getting this crystalline form II (see published international application WO 98/04573 and WO 98/31699), however, the problem inherent in this method is low productivity.

Alternatively, crystals of form II can be obtained by recrystallization of the crystals of form I from a mixture of chloroform/simple isopropyl ether (see Kerck Index 12thed., pp.395) or by recrystallization of the crystals of form I of the organic solvent or mixture of organic solvent and water with a moderate output (see published international application WO 98/04574). In accordance with these methods, because the transformation of the crystals of form I crystals of form II is not accompanied by an increase in the purity of the crystals of form I with a high degree of purity must be obtained in advance from the crude clarithromycin by reducing the output of clarithromycin and above the deposits with a high yield of clarithromycin in the form of crystals of form II, high purity.

The invention

In accordance with the foregoing, a first object of the present invention is to develop a method of producing crystals of clarithromycin form II, high purity and high yield.

Another object of the invention is a new intermediate compounds obtained in accordance with the specified method.

In accordance with one aspect of the invention, a method for receiving clarithromycin in the form of crystals of form II (formula I), comprising the following stages:

(a) processing of clarithromycin with no pharmaceutical purity, methanesulfonic acid in the mixture is miscible with water, an organic solvent and water to obtain this three-hydrate crystalline nelfinavir clarithromycin of formula (II); and

(b) neutralization of the crystal three-hydrate nelfinavir clarithromycin obtained at stage (a), an aqueous solution of ammonia in the mixture is miscible with water, an organic solvent and water, where the term “clarithromycin with no pharmaceutical purity” refers to clarithromycin any purity or any degree of crystallinity, including crude product, �232D/img_data/78/787146.gif">

In accordance with another aspect of the invention an improved method of receiving clarithromycin with no pharmaceutical purity, comprising the following stages:

protection 9-oximes hydroxy-group 9-oxime erythromycin And formula (IV) or its salt trepiline group and the 2’- and 4’-hydroxyl groups trimethylsilyl groups with 9-O-triperoxide 2’, 4’-O-bis(trimethylsilyl)erythromycin And formula (IIIb);

the interaction of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)erythromycin a with meteorous agent with 9-O-triperoxide 2’, 4’-O-bis(trimethylsilyl)-6-O-methyl-erythromycin a of formula (S); and removing the protective groups and the oxime group transformation of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin:

In accordance with another aspect of the invention proposed crystalline trihydrate nelfinavir clarithromycin of formula (II); and 9-O-triperoxonane derivative of erythromycin And formula (III):

in which

R1represents hydrogen or methyl group; and

R2

Brief description of drawings

The above and other objects and features of the invention will be clear from the following description of the invention, together with the following accompanying drawings, where:

In figures 1 and 2 shows the infrared spectrum and the spectrum of the powder diffraction spectroscopy x-ray of three-hydrate of clarithromycinresistant, respectively.

In figures 3 and 4 shows the infrared spectrum and the spectrum of the powder diffraction spectroscopy x-ray of clarithromycin in the form of crystals of form II, respectively.

Detailed description of the invention

The term “clarithromycin with no pharmaceutical purity”, in the sense in which it is used in the description refers to clarithromycin any purity or any degree of crystallinity, and to clarithromycin in the raw state, obtained in accordance with the method of its production.

According to the invention crystalline trihydrate nelfinavir clarithromycin of formula (II) are obtained by processing claritromicina not possessing pharmaceutical purity obtained using methanesulfonic acid in cm is t or suspended in a mixture of miscible with water, an organic solvent, such as acetone, ethanol or isopropanol, and water at a temperature of from room temperature up to 45C. solvent Mixture contains water in an amount more than 3 equivalents, preferably from 3 to 15 equivalents, per used clarithromycin.

After that methansulfonate acid, undiluted or dissolved in the same solvent mixture, is added to the suspension in an amount of from 0.9 to 1.1 equivalents, based on the amount of clarithromycin. The mixture can be maintained at a temperature of from room temperature up to 45With over 30 minutes to 3 hours. The resulting mixture is cooled to a temperature of from 0With up to 5C, and stirred for 1 to 5 hours. In conclusion, the formed crystals are filtered, washed with the same mixture of solvents and dried at a temperature of from room temperature up to 45With thus the crystalline trihydrate nelfinavir clarithromycin.

If necessary, the thus obtained crystals of three-hydrate nelfinavir clarithromycin can be further recrystallized from the same solvent mixture in the usual way.

Trihydrate mesilate the water-organic solvent and water, and clarithromycin the form of crystals of form II may be subjected to recrystallization.

In particular, the trihydrate nelfinavir clarithromycin dissolved in a mixture miscible with water, an organic solvent and water at room temperature. Then the solution is filtered to remove impurities, and the filtrate is neutralized to pH values from 9 to 12 by adding an aqueous solution of ammonia. The resulting solution was stirred for 30 minutes or more in order to cause precipitation of crystals. In conclusion, the precipitated crystals filtered off, washed with the same mixture of solvents and dried at a temperature of from room temperature to 60With receiving clarithromycin in the form of crystals of form II.

Miscible with water, an organic solvent, which can be used in accordance with the above method represents the acetone, ethanol, isopropanol or a mixture thereof.

Water and miscible with water, an organic solvent can be mixed in a volume ratio of 30:70 to 70:30.

The method which is the subject of the invention is very simple and allows you to get clarithromycin in the form of crystals of form II with high yield at insignificant cost of pbecause pharmaceutical purity, which is a high-performance, high production method of clarithromycin in the form of crystals of form II, if it is combined with the above method of obtaining clarithromycin in the form of crystals of form II.

The first stage of this improved method of obtaining clarithromycin with no pharmaceutical purity, can be done thus, as shown in figure 1:

Scheme 1

Namely, 9-O-traprock eritromicina And formula (IIIa) can be obtained by the interaction of 9-oxime erythromycin And formula (IV) with tetrafluoroborates of trapelia in an aprotic polar solvent in the presence of a base at a temperature from 0 to 60C.

Tetrafluoroborate of trapelia can be used in an amount of from 1 to 1.3 equivalents per 9-oxime erythromycin And formula (IV).

Examples of the aprotic polar solvent, which appropriately may be used for the above reaction are tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetonitrile, N,N-dimethylformamide, dichloromethane or a mixture thereof, and the base may be selected from the group comprising the tertiary amine, for example tree the he-5-ene and 1,4-diazabicyclo[2.2.2]octane; sodium carbonate; potassium carbonate; sodium hydroxide; potassium hydroxide, tert-piperonyl potassium, and sodium hydride. The base can be used in an amount of from 1 to 1.5 equivalents based on the number of 9-oxime erythromycin And formula (IV).

Then, 9-O-traprock 2’, 4’-O-bis(Turkmeneli)erythromycin And formula (IIIb) is obtained by interaction of 9-O-triperoxide erythromycin And formula (IIIa) obtained as described above, with ammonium chloride and 1,1,1,3,3,3-hexamethyldisilazane in an organic solvent such as N,N-dimethylformamide or acetonitrile, at temperatures from room temperature up to 50C. the Amount of ammonium chloride and 1,1,1,3,3,3-hexamethyldisilazane is from 0.5 to 1.5 equivalents and 2 to 4 equivalents, respectively, based on the number of 9-O-triperoxide erythromycin And formula (IIIa).

Alternatively, compound IIIb can be obtained as follows.

9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin And formula (V) are obtained by the interaction of 9-oxime erythromycin And formula (IV) with ammonium chloride and 1,1,1,3,3,3-hexamethyldisilazane in organic acid, such as N,N-dimethylformamide, at a temperature from room temperature up to 50

Then 9-O-traprock 2’,4’-O-bis(trimethylsilyl)-erythromycin a of formula (IIIb) is obtained by interaction of 9-oxime 2'and 4’-bis(trimethylsilyl)erythromycin And formula (V) obtained above, with tetrafluoroborates of trapelia in an aprotic polar organic solvent in the presence of a base at a temperature from 0 to 60C. the reaction Conditions and the solvent and the base used for this reaction can be exactly the same as when obtaining the compounds of formula (IIIa).

In the second stage 9-O-traprock 2’,4’-O-bis(trimethylsilyl) erythromycin And formula (IIIb) obtained in the first stage, was identified in using the motivating agent, for example, under the conditions in the environment of a solvent in the presence of a base to obtain 9-O-traprock 2’,4’-O-bis(trimethylsilyl) -6-O-methylerythromycin And formula (S).

Methyliodide can be used in an amount of from 1 to 1.5 equivalents, based on the number of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)erythromycin And formula (IIIb).

Examples of the solvent which suitably can be used in the above reaction is a mixture of tetrahydrofur can be used in the above reaction, include potassium hydroxide; potassium hydride; tert-piperonyl potassium; sodium hydride and a mixture thereof. The base can be used in an amount of from 1 to 1.3 equivalents per 9-O-traprock 2’,4’-O-bis(trimethylsilyl)erythromycin And formula (IIIb). In that case, when a base is used, the potassium hydroxide is preferred powder of potassium hydroxide with a particle size of 600 μm.

In conclusion, 9-O-traprock 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And formula (C) obtained in the previous phase is treated with formic acid and sodium bisulfite in aqueous alcoholic solvent in order to remove the protective group and oximo group 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And formula (IIIc), at a temperature from room temperature up to the boiling point of the used solvent, obtaining with clarithromycin.

The amount of formic acid and sodium bisulfite is from 1 to 2 equivalents and 2 to 5 equivalents, respectively, based on the number of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And formula (IIIc).

Aqueous-alcoholic solvent which can be suitably used for the panel, and water in a volume ratio of 2:1 to 1:2.

The above-described method of obtaining clarithromycin, which has no need for pharmaceutical use quality is much simpler and is characterized by a high yield of pure product, compared with the methods known from the prior art.

The following reference examples and examples are intended to further illustrate the invention without limiting its scope; and experimental methods used in accordance with the invention, can be carried out in accordance with the reference example and examples given below in the description, unless otherwise specified.

In addition, the percentages indicated for solids in a mixture of solids, liquids in liquids and solids in liquids are for ratios of wt./wt., about./about. and wt./about., accordingly, unless specifically indicated otherwise.

Reference example: 9-oxime erythromycin And

to 31.9 g of Erythromycin And dissolved in 50 ml of methanol. Add to 15.1 g of hydroxylamine-Hcl and 15.1 ml of triethylamine and refluxed for 24 hours. The resulting solution is cooled to temperatures below 5 °

Obtained, as indicated above, 9-oxime-Hcl erythromycin And suspended in 100 ml of methanol and add 20 ml of concentrated aqueous ammonia. The resulting solution is stirred at a temperature of from 0 to 5With in a few hours. After that, the formed solid is filtered off, washed with water and dried, thus obtaining 26,0 g specified in the title compound with a yield of 80%.

Example 1: get a 9-O-triperoxide erythromycin And [stage (A-1-1)]

11,23 g of 9-oxime erythromycin a, obtained in accordance with the reference example, dissolved in 75 ml of N,N-dimethylformamide. Add 3,20 g tetrafluoroborate of trapelia 3.14 ml of triethylamine, the resulting mixture is stirred at a temperature of from 30 to 40With over 4 hours. The resulting solution was cooled to room temperature and add 200 ml of water, then extracted twice with 100 ml of ethyl acetate. The organic layers are combined washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining of 12.6 g of 9-O-triperoxide erythromycin in the form of a foamed substance o the tion in the title compound as a white powder, with the release of 87%.

So pl. 120-122

1H-NMR (CDCl3, ppm):of 6.68 (m, 2H, were tracked 4’’-H and 5’’-H), 6,32 (m, 2H, were tracked 3’’-H and 6’-H), 5,67 (m, 2H, were tracked 2’’-H and 7’-H), 5,12 (DD, 1H, 13-H), is 4.93 (d, 1H, 1’-H), 4,56 (t, 1H, were tracked 1’’-H), 4,43 (d, 1H, 1’-H), 4,07 (DD, 1H, 3-H), was 4.02 (DQC., 1H, 5’-H), to 3.67 (d, 1H, 11-H), 3,57 (d, 1H, 5-H), 3,50 (ddcv., 1H, 5’-H), 3,49 (DQC., 1H, 10-K) to 3.33 (s, 3H, cladinose 3’-och3) at 3.25 (DD, 1H, 2’-H), 3.04 from (DD, 1H, 4’-H), 2,92 (ddcv., 1H, 8-H), 2,65 (DQC., 1H, 2-H), a 2.45 (DDD, 1H, 3’-H), of 2.38 (DD, 1H, 2’-Heq), 2,30 (d, 6N, desosamine 3’-N (CH3)2), 2,23 (ddcv., 1H, 4-H), 2,03~1,45 (m, 6N, 4’-Heq, 7-H2, 2’-HOhand 14-H2), was 1.43 (s, 3H, 18-H), to 1.32 (d, 3H, 6’-H), 1.26 in (s, 3H, 7’-H), 1,21~1,02 (m, N, 4’-Hax, 6’-H3, 16-H3, 20-H3, 21-H3, 17-H3and 19-H3) to 0.85 (t, 3H, 15-H3).

13C-NMR (Dl3, ppm):175,5 (C9), 172,9 (C1), to 131.4 and 131, 5mm (were tracked C4’ and C5’), 125,2 and 125.4 (were tracked C3’ and C6’’), to 124.4 and output reached 125.5 (were tracked C2’ and C7’’), 103,4 (C1’), 96,7 (C1’), with 83.6 (C5), 80,4 (C6), 78,5 (C3), 78,1 (were tracked Cl’), 77,3 (C4’), 75,7 (C13), 74,7 (C12), 73,1 (C3’), 71,4 (C2’), 71,0 (C11), 69,2 (C5’), 66,0 (C5’), 65,9 (C3’), a 49.9 (C8’), 45,1(C2) 40,7 (C7’ and C8’), 39,4 (C4), 38,2 (C7), 35,5 (C2’), 33,4 (C8), 29,1 (C4’), 27,3 (C10), 26,8 (C19), 21,9 (C6’), 21,8 (C7’), 21,5 (C14), 19,1 (C18), 19,1 (6’), 16,6 (C21), 16,5 (C16), And 14.9 (Sophianou in example 1, with the exception that instead of triethylamine use 3.11 g of potassium carbonate, while receiving 10.7 g specified in the title compound as a white powder with a yield of 85%.

Physico-chemical characteristics and data of NMR spectroscopy for this product is identical characteristics and data obtained for the compounds synthesized in accordance with example 1.

Example 3: 9-O-triperoxide erythromycin And [stage (a-1-1)]

11,23 g of 9-oxime erythromycin a, obtained in accordance with the reference example, dissolved in 75 ml of N,N-dimethylformamide and cooled to 0C. Add 2,19 g of tert-butoxide potassium and the resulting mixture is stirred for 15 minutes. Then there add 3,29 g tetrafluoroborate of trapelia and stirred at a temperature of from 0 to 5C for 2 hours, then repeat the procedure described in example 1, obtaining 11,33 g specified in the title compound as a white powder with a yield of 90%.

Physico-chemical characteristics and data of NMR spectroscopy for this product is identical characteristics and data obtained for the compounds synthesized in accordance with example 1.

Example 4: 9-O-triperoxide erythromyci the foreign Ministry used tetrahydrofuran, and interaction is carried out for 3 hours, while receiving 11,46 g specified in the title compound as a white powder with a yield of 91%.

Physico-chemical characteristics and data of NMR spectroscopy for this product is identical characteristics and data obtained for the compound synthesized according to example 1.

Example 5: 9-O-triperoxide erythromycin And [stage (a-1-1)]

11,23 g of 9-oxime erythromycin a, obtained in accordance with the reference example, dissolved in 120 ml of acetonitrile. Add 3,20 g tetrafluoroborate of trapelia, then added dropwise 3,14 ml of triethylamine, with increasing temperature from 30 to 40C. the resulting solution was stirred at the same temperature for 4 hours and cooled to 0C, and then stirred for 1 hour. The formed solid is filtered off, washed with cold acetonitrile and dried to obtain 11,83 g specified in the title compound as a white powder with a yield of 94%.

Physico-chemical characteristics and data of NMR spectroscopy for this product is identical characteristics and data obtained for the compound synthesized according to example 1.

Example 6: the floor is of Irina And, obtained in accordance with example 1, is dissolved in 75 ml of N,N-dimethylformamide. Added 1.20 g of ammonium chloride and 6.3 ml of 1,1,1,3,3,3-hexamethyldisilazane, then stirred the mixture at a temperature varying from 30 to 40With over 4 hours. The resulting solution was cooled to room temperature and add 200 ml of water, then extracted twice using 100 ml of ethyl acetate. The organic layers are combined and washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 14.5 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)erythromycin a in the form of foamed substance with a yield of 98%.

1H-NMR (Dl3, ppm):of 6.68 (m, 2H, were tracked 4’’-H and 5’’-H), 6.30-in (m, 2H, were tracked 3’’-H and 6’-H), to 5.66 (m, 2H, were tracked 2’’-H and 7’-H), 5,10 (DD, 1H, 13-H), the 4.90 (d, 1H, 1’-H), a 4.53 (t, 1H, were tracked 1’-H), and 4.40 (d, 1H, 1’-H), 4,25 (DQC., 1H, 5’-H), 4,19 (DD, 1H, 3-H), of 3.69 (d, 1H, 11-H), 3,66 (ddcv., 1H, 5’-H), 3,62 (DQC., 1H, 10-H), to 3.58 (d, 1H, 5-H), of 3.32 (s, 3H, cladinose 3’-och3), 3,18 (DD, 1H, 2’-H), and 3.16 (DD, 1H, 4’-H), 2,85 (ddcv., 1H, 8-H), 2,70 (DQC., 1H, 2-H), to 2.55 (DDD, 1H, 3’-H), 2,39 (DD, 1H, 2’-Heqin ), 2.25 (d, 6N, desosamine 3‘-N (CH3)2), 2,00-of 1.40 (m, 7H, 4-H, 4’-Heq, 7-H2, 2’-H,h and 14-H2), to 1.42 (s, 3H, 18-H), 1,/sub> and 19-H3), of 0.87 (t, 3H, 15-H3) 0,16 (s, N, 4’-OSi(CH3)3), 0,11 (s, N, 2’-OSi(CH3)3).

13C-NMR (CDCl3, ppm):176,1 (C9), 172,6 (Cl), 131, 6mm and 131,3 (were tracked 04’’ and C5’), 125,2 and 125,0 (were tracked C3’ and C6’’), of 124.7 and of 124.7 (were tracked C2’ and C7’’), 103,1 (Cl’), 97,0 (Cl’), 81,8 (C5), 81,3 (C6), 79,8 (C3), 78,2 (and Cl’’), 77,3 (C4’), 75,9 (C13), 74,7 (C12), 73,7 (C3’), 73,6 (C2’), 71,0 (C11), 68,1(C5’), 65,5 (C5’), 65,3 (C3’), 50,1 (C8’), 45,1 (C2) 41,4 (C7’ and C8’), 40,3 (C4), 38,9 (C7), 36,3 (C2’), 33,5 (C8), 30,1 (C4’), 27,4 (C10), 26,8 (C19), 22,6 (C6’), 22,2 (C7’), 21,6 (C14), 19,8 (C18), 19,0 (6’), 16,6 (C21), 16,2 (C16), 14,8 (C20), 11,1 (C15), 10,0 (C17), 1,41 (4’-OSi(CH3)3), 1,31 (2’-OSi(CH3)3).

Example 7: 9-O-tropinskiy 2’,4’-O-bis(trimethylsilyl)erythromycin a from 9-oxime erythromycin A [stage (a-1-1) and (a-1-2)]

11,23 g of 9-oxime erythromycin a, obtained in accordance with the reference example, dissolved in 75 ml of N,N-dimethylformamide and cooled to 0C. Add 2,19 g of tert-butoxide potassium and the resulting mixture is stirred for 15 minutes. Then there add 3,20 g tetrafluoroborate of trapelia and stirred at a temperature of from 0 to 5C for 3 hours. After this type of 1.34 g of ammonium chloride and 10.0 ml of 1,1,1,3,3,3-hexamethylol. The resulting solution was cooled to room temperature and add 200 ml of water, then extracted twice using 100 ml of ethyl acetate. The organic layers are combined and washed twice with water, dried over magnesium sulfate and concentrated under reduced pressure, thus obtaining 13.5 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)erythromycin a in the form of foamed substance with a yield of 90%.

Data1H-NMR of this product is identical to the data obtained for the compound synthesized according to example 6.

Example 8: a 9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin A [stage (a-2-1)]

32,8 g 9-oxime-Hcl erythromycin And received in accordance with a reference example, dissolved in 125 ml of N,N-dimethylformamide. Added 1.13 g of ammonium chloride and 23 ml of 1,1,1,3,3,3-hexamethyldisilazane, stirred the mixture at a temperature varying from 40 to 45With over 2 hours. Gradually add 15 ml of 4n solution of sodium hydroxide, 100 ml of water and 50 ml of hexane, the mixture is stirred for 2 hours. The formed solid is filtered off, while receiving of 31.4 g of 9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin And with the release of 81%.

Example 9: 9 lilil)erythromycin A, obtained in accordance with example 8, dissolved in 40 ml of tetrahydrofuran and cooled to 0C. Added 0.52 g of 60% sodium hydride and the resulting mixture is stirred for 20 minutes. Then add there 2.14 g of tetrafluoroborate of trapelia and stirred at a temperature of from 0 to 5C for 3 hours, then repeat the procedure according to example 6, while receiving 9,44 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)erythromycin a in the form of a white foam substance with a yield of 96%.

Data1H-NMR spectroscopy for this product is identical to the data obtained for the compound synthesized according to example 6.

Example 10: 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)erythromycin A [stage (2-2)]

of 13.4 g of 9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin a, obtained in accordance with example 8, and 2.67 g of tetrafluoroborate of trapelia dissolved in 50 ml of dichloromethane at room temperature. Then added to 2.3 ml of triethylamine and stirred at the same temperature for 3 hours, after which water is added. The organic layers are combined and washed with water, dried over magnesium sulfate and concentrated under reduced pressure receiving IOM 99%.

Data1H-NMR spectroscopy for this product is identical to the data obtained for the compound synthesized according to example 6.

Example 11: 9-O-triperoxide 2’,4’-O-bis-(trimethylsilyl)-6-O-methylerythromycin And

14,75 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-erythromycin a, obtained according to the preceding examples, dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of DMSO and cooled toC. Add there 1,21 ml under the conditions and 1.09 g of 85% potassium hydroxide. The resulting mixture is stirred at a temperature of from 0 to 5C for 4 hours. Add 150 ml of water and extracted twice with 100 ml of atelierista. The organic layers are combined and washed twice with water, dried over magnesium sulfate, and then concentrated under reduced pressure, thus obtaining 14,71 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And in the form of a white foam substance with a yield of 98%.

lH-NMR (Dl3, ppm):of 6.65 (m, 2H, were tracked 4’’-H and 5’’-H), 6,17 (m, 2H, were tracked 3’’-H and 6’-H), 5,61 (m, 2H, were tracked 2’’-H and 7’-H), 5,11 (DD, 1H, 13-H), 4,91 (d, 1H, 1’-H), of 4.57 (t, 1H, were tracked 1’’-H), 4,43 (d, 1H, 1’-H), 4,sub>3), to 3.09 (s, 3H, 6-och3), 3,19 (DD, 1H, 2’-H), and 3.16 (DD, 1H, 4’-H), 2,87 (ddcv., 1H, 8-H), 2,60 (DQC., 1H, 2-H), 2,59 (DDD, 1H, 3’-H), of 2.38 (DD, 1H, 2’-Heqin ), 2.25 (d, 6N, desosamine 3’-N (CH3)2), 2,00~of 1.41 (m, 7H, 4-H, 4’-Heq, 7-H2, 2’-HOhand 14-H2), of 1.46 (s, 3H, 18-H) of 1.28 (d, 3H, 6"-H), 1,18 (c, 3H, 7"-H), 1,22-of 0.95 (m, 19H, 4'-Hax, 6'-H3, 16-H3, 20-H3, 21-H3, 17-H3and 19-H3) to 0.85 (t, 3H, 15-H3), 0,16 (s, N, 4"-OSi(CH3)3), 0,11 (s, N, 2’-OSi(CH3)3).

13C-NMR (Dl3, ppm):176,3 (C9), 171,4 (Cl), to 131.4 and to 131.4 (were tracked C4’ and C5’), 126,0 and 125,1 (were tracked C3 and C6’1), 123,4 and 123.1 (were tracked C2’ 07’’), 103,0 (C1'), 96,6 (C1’), 81,3 (C5), 79,4 (C6), 79,3 (were tracked IG’), 78,4 (C3), 77,1 (C4’), 77,0 (C13), 74,3 (C12), 73,7 (C3’), 73,6 (C2’), 71,5 (C11), 67,6 (C5’), 65,5 (C5’), 65,5 (C3’), 51,5 (6-och3), 50,1 (C8’), 45,8 (C2) 41,4 (C7’ and C8’), 40,0 (C4), 38,2 (C7), 36,2 (C2’), 33,4 (C8), 30,0 (C4’), 26,7 (C10), 22,6 (C19), 21,6 (C6’), 22,4 (C7’), 20,6 (C14), 19,8 (C18), 19,1 (6’), 16,6 (C21), 16,5 (C16), 15,5 (C20), 11,1 (C15), 10,1 (C17), 1,46 (4’-OSi(CH3)3), 1,29 (2’-OSi(CH3)3).

Example 12: 9-O-triperoxide 2’,4’-O-bis-(trimethylsilyl)-6-O-methylerythromycin And from 9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin And

8,93 g 9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin a, obtained soglasen tert-butoxide potassium and the resulting mixture is stirred for 20 minutes. Then add 2.14 g of tetrafluoroborate of trapelia and stirred at a temperature of from 0 to 5C for 3 hours. Add to a mixture of 40 ml of dimethyl sulfoxide, 0,81 ml under the conditions and 0.73 g of 85% powdered potassium hydroxide, stirred for 4 hours at a temperature of from 0 to 5C.

Then repeat the selection procedure described in example 11, while receiving 9,27 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And in the form of a white foam substance with a yield of 93%.

Data1H-NMR spectroscopy of this product is identical to the data obtained for the compound synthesized according to example 11.

Example: the study of the properties of

The crude products obtained in accordance with the above-described stages of methylation of 6-hydroxy groups of 9-O-triperoxide 2’,4’-O-bis (trimethylsilyl) erythromycin A, were analyzed by high performance liquid chromatography (HPLC) to assess the selectivity of 6-O-methylation and comparison with data obtained for the respective stages, carried out according to the prior art, the results are shown in table. 1.

As evidenced by the above results and 6-hydroxy groups is characterized by the greatest selectivity.

Example 13. Obtaining clarithromycin

13.3 g of 9-O-triperoxide 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And obtained in accordance with example 11, was dissolved in 70 ml of ethanol. Gradually add 0.75 ml of formic acid, 70 ml of water and of 4.16 g of sodium bisulfite, and the resulting mixture is refluxed for 2 hours. The resulting solution was cooled below 10And I add 140 ml of water and 50 ml of hexane. Bring the pH of the resulting solution to 10 by adding 2 n sodium hydroxide solution. The mixture is stirred at a temperature below 10C for 1 hour and then filter the resulting solid, washed with water, then dried at approximately 50With, while receiving 7,46 g of the crude clarithromycin in the form of a white powder with a yield of 75%.

So pl.: 220~223(For example, in the literature for crystals of form I so pl. is 222~225C).

1H-NMR (Dl3, ppm):of 5.06 (DD, 1H, 13-H), to 4.92 (d, 1H, 1’-H), of 4.44 (d, 1H, 1’-H), was 4.02 (DQC., 1H, 5’-H), of 3.78 (DD, 1H, 3-H), (DQC., 1H, 5’-H), of 3.77 (d, 1H, 11-H), to 3.67 (d, 1H, 5-H), 3,57 (DDCS., 1H, 5’-H), to 3.33 (s, 3H, 3’-och3), 3,20 (DD, 1H,-N), is 2.37 (d, 1H, 2’-Hq), 2,28 (s, 6N, 3’-N (CH3)2), from 2.00 and 1.80 (m, 3H, 4-H,7-H2, 14-H1), a 1.75-of 1.40 (m, 3H, 4’-Heq, 2’-HOhand 14-H1), of 1.41 (s, 3H, 18-H) of 1.13 (s, 3H, 6-CH3), is 1.31 (d, 3H, 6’-H3), 1,30-of 1.05 (m, 22N, 7’-H3, 4’-HOh6’-N3, 16-H3, 20-H3, 21-H3, 17-H3and 19-H3), is 0.84 (t, 3H, 15-H3).

13C-NMR (Dl3, ppm):221,0 (C9), 175,9 (C1), 102,8 (C1), 96,0 (C1’), 80,7 (C5), 78,4 (C6), 78,4 (C4’), 77,9 (C3), 76,6 (C13), 74,2 (C12), 72,6 (C3’), 70,9 (C2’), 69,0 (C11), 68,7 (C5’), 65,8 (C5’), 65,5 (C3’), 50,6 (6-och3), 49,4 (C8’), 45,2 (C8), 45,0 (C2), 40,2 (C7’ and C8’), 39,4 (C7), 39,3 (C4), 37,2 (C10), 34,8 (C2’), 28,5 (C4’), 21,4 (C6’), 21,4 (C7’), 21,0 (C14), 19,7’ (C18), 18,6 (6’), 17,9 (C19), 15,9 (C21), 15,9 (C16), 12,2 (C20), 10,6 (C15), And 9.0 (C17).

Example 14. Obtaining three-hydrate of clarithromycinresistant

11.2 g of clarithromycin (15 mmol) having a purity of 97%, dissolved in 32 ml of 95% acetone and added dropwise methanesulfonyl acid, and then stirred at room temperature for 1 hour. Then, the resulting suspension is cooled to 0C and stirred for 3 hours. The formed crystals are filtered, washed with cold acetone and dried at 45With, while receiving 10.3 g Krista is

Moisture content: 6,2% (Karl-Fischer, theoretical moisture content for three-hydrate is 6,02%).

IR (KBR, cm-1): 3428, 2978, 2939, 1734, 1686, 1459, 1378, 1347, 1170, 1110, 1077, 1051, 1010, 954, 908, 892, 780.

1H-NMR (CDCl3, ppm):5,07 (DD, 1H, 13-H), 4,91 (d, 1H, 1’-H), 4,60 (d, 1H, 1’-H), 3,98 (DQC., 1H, 5’-H), 3,76 (ddcv., 1H, 5’-H), 3,76 (d, 11N, 1-N), and 3.72 (DD, 1H, 3-H), 3,70 (DD, 1H, 5-H), 3,55 (DDD, 1H, 3’-H), 3,47 (DQC., 1H, 2’-H), to 3.35 (s, 3H, 3’-och3), of 3.07 (DD, 1H, 4’-H), 3.04 from (s, 3H, 6-och3), 3,03 (s, 1H, 10-H), with 2.93 (s, 6N, 3’-N (CH3)2), 2,87 (DQC., 1H, 8-H), 2,78 (s, 3H, CH3SO-3), 2,58 (DQC., 1H, 2-H), is 2.37 (DD, 1H, 2’-Heq), of 2.08 (DDD, 1H, 4’-Heq), 1,94 (ddcv., 1H, 4-H) of 1.93 (DD, 1H, 7-HOh), with 1.92 1.48 (ddcv., 2H, 14-H), 1,72 (DD, 1H, 7-Heq), 1,59 (ddcv., 1H, 2’-HOh), of 1.41 (s, 3H, 18-H), to 1.31 (d, 3H, 6’-H), 1,30 (DDD, 1H, 4’-HOh), 1,25 (s, 3H, 7’-H) of 1.23 (d, 3H, 6’-H), to 1.21 (d, 3H, 16-H), 1.14 in (d, 3H, 19-H) of 1.13 (d, 3H, 20-H) of 1.12 (s, 3H, 21-H) of 1.09 (d, 3H, 17-H), or 0.83 (t, 3H, 15-CH3).

13C-NMR (CDCl3, ppm):221,3 (9-C), 176,4 (1-C), 102,4 (1’-C), 97,0 (1’-C) 82,3 (5-C) 79,5 (3-C) TO 78.9% (6-C), TO 78.3 (4’-C), 77,4 (13-C), 74,9 (12-C), 73,6 (3’-C) 70,6 (2’-C) 69,7 (11-C), 67,7 (5’-C) 66,7 (5’-C), 66,1 (3’-C), 51,1 (22-C), A 49.9 (8’-C) 45,7 (8-C) 45,6 (2-C), 39,8 (7’, 8’-and 7-With), 39,7 (4-0, 38,0 (10-C) 35,7 (2’-C), 31,6 (4’-C), 22,0 (6’-C) 21,6 (7’-C and 14-C) 20,5 (18-C) And 19.2 (6’-C), 18,5 what about clarithromycin, the results are shown in table 2.

The infrared spectrum and the spectrum of the powder diffraction spectroscopy x-ray of three-hydrate of clarithromycinresistant shown in Fig.1 and 2, respectively.

Examples 15 and 16: obtaining three-hydrate of clarithromycinresistant

In each of examples 15 and 16 repeat the procedure described in example 14, except that instead of acetone using various organic solvents. The results are shown in table.2.

Example 17: recrystallization of three-hydrate of clarithromycinbased 14.0 g of three-hydrate of clarithromycinresistant having a purity of 92%, suspended in 50 ml of 95% ethanol is refluxed until complete dissolution, cooled to 0C and stirred for 4 hours. After that, the formed crystals are filtered, washed with acetone, cooled to 0With, and dried at 45With, while receiving 12.0 g of purified crystalline three-hydrate of clarithromycinresistant (purity: 97.5 per cent, yield: 86% moisture: 6,2%).

Example 18: recrystallization of three-hydrate of clarithromycinresistant

Repeat the procedure, describe what the GLA.3.

Example 19. Obtaining clarithromycin in the form of crystals of form II of the three-hydrate of clarithromycinresistant

14.0 g of the three-hydrate of clarithromycinresistant (purity 96(C) dissolved in a mixture of 42 ml of ethanol and 84 ml of water and filtered to remove insoluble ingredients. Add to the filtrate is added dropwise 4.8 ml of concentrated aqueous ammonia solution and stirred for 3 hours. After that, the formed crystals are filtered and dried overnight in air at 55With, while receiving 11.3 g of clarithromycin in the form of crystals of form II (purity: 97.2 per cent, yield: 97%).

The infrared spectrum and the spectrum of the powder diffraction spectroscopy x-ray of clarithromycin in the form of crystals of form II is shown in figures 3 and 4, respectively.

Example 20. Obtaining clarithromycin in the form of crystals of form II from the crude clarithromycin

br93.1 g of the crude clarithromycin (0,124 mol) is dissolved in 260 ml of 95% acetone and filtered to remove nerastvorim ingredients. Add to the filtrate is added dropwise 10 g methanesulfonic acid (0,105 mol) and stirred for 1 hour. After that obtained avchina the crystals are filtered, washed with cold acetone and dried at 45With the receiving of 87.5 g of crystalline three-hydrate of clarithromycinresistant (purity: 93%, yield: 78%, and moisture content: 6,4%).

of 87.5 g of three-hydrate of clarithromycinresistant (0,097 mol) is suspended in 306 ml of 95% ethanol is refluxed for 30 minutes to achieve complete dissolution, and then slowly cooled to 0With under stirring. The mixture is then stirred at 0C for 4 hours, and the resulting crystals filtered off, washed with acetone, cooled to 0With, and dried at 45With, receiving at the same time 74.4 g of purified crystalline three-hydrate of clarithromycinresistant (purity: 97%, yield: 85%, and moisture content: 6.1 per cent).

74,4 g three-hydrate of clarithromycinresistant (0,083 mol), obtained as described above, suspecious in a mixture of 220 ml of ethanol and 440 ml of water, and filtered to remove any insoluble ingredients. Add to the filtrate is added dropwise 25 ml of concentrated aqueous ammonia solution and stirred at room temperature for 3 hours. After that, the formed crystals tfilter the crystal form II (purity: 98,0%, and zhod: 97%).

Comparative example

br93.1 g of the crude clarithromycin (0,124 mol) is recrystallized from 600 ml of ethanol and dried, thus obtaining to 65.2 g of clarithromycin in the form of crystals of form I (purity: 94%, yield: 70%), in accordance with the method described in published international application WO 98/04573.

to 65.2 g of clarithromycin in the form of crystals of form I (0,087 mol) is suspended in 510 ml of ethanol and refluxed for 1 hour in order to dissolve a large part of the crystals. The solution is subjected to hot filtration to remove nerastvorim ingredients, then the filtrate is cooled to 10C and stirred for 2 hours. After that, the formed crystals are filtered and dried at 50With the receiving of 54.1 g of peeled clarithromycin in the form of crystals of form I (purity: 97.1 per cent, yield: 83%).

Then of clarithromycin in the form of crystals of form I get clarithromycin in the form of crystals of form II in accordance with the method disclosed in published international application WO 98/04574.

Namely, to 54.1 g of peeled clarithromycin in the form of crystals of form I (0,072 mol) is suspended in 270 ml of ethyl acetate and boiled with reverse holodilnikah 40 ml of ethyl acetate and refluxed. The solution is cooled to 50With, add 270 ml simple isopropyl ether and cooled to 5C. the Resulting crystals are filtered and dried, thus obtaining of 41.7 g of clarithromycin in the form of crystals of form II (purity: 97,2, yield: 77%).

Because embodiments of the invention described and illustrated by examples, it is obvious that, without departing from the scope of the subject invention can be implemented various changes and modifications, which is limited only by the scope defined by the attached claims.

Claims

1. The method of obtaining clarithromycin in the form of crystals of form II (formula I), comprising the following stages: (a) treatment of clarithromycin methanesulfonic acid in the mixture is miscible with water, an organic solvent and water to obtain this three-hydrate crystalline nelfinavir clarithromycin of formula (II); (b) neutralizing the crystal three-hydrate nelfinavir clarithromycin obtained at stage (a), an aqueous solution of ammonia in the mixture is miscible with water, an organic solvent and water:

3. The method according to p. 2, where 9 is About-traprock 2’,4’-O-bis(trimethylsilyl)erythromycin And formula (IIIb) are obtained by the process comprising the following stages: interaction 9-the oxime of erythromycin And c tetrafluoroborates of trapelia in an aprotic polar solvent in the presence of a base at a temperature 0 - 60°C to obtain 9-About-tropological erythromycin A; processing 9-About-tropological erythromycin And ammonium chloride and 1,1,1,3,3,3-hexamethyldisilazane in an organic solvent at a temperature from room temperature to 50°C.

4. The method according to p. 2, where 9 is About-traprock 2’,4’-O-bis(trimethylsilyl)araromi is its salts with ammonium chloride and 1,1,1,3,3,3-hexamethyldisilazane in an organic solvent at a temperature from room temperature up to 50°C, obtaining this 9-oxime 2’,4’-O-bis(trimethylsilyl)erythromycin A; the interaction of 9-oxime 2’,4’-O-bis(trimethylsilyl)-erythromycin a with tetrafluoroborates of trapelia in an aprotic polar solvent in the presence of a base at a temperature of 0 to 60°C.

5. The method according to p. 3 or 4, where the aprotic polar solvent is a tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetonitrile, N,N-dimethylformamide, dichloromethane or a mixture thereof.

6. The method according to p. 3 or 4, where the base is a triethylamine, Tripropylamine, diethylethanolamine, tributylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane; sodium carbonate; potassium carbonate; sodium hydroxide; potassium hydroxide, tert-piperonyl potassium, sodium hydride or a mixture thereof.

7. The method according to p. 2, where 9 is About-traprock 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And formula (S) produced by interaction of 9-O-tropological 2’,4’-O-bis(trimethylsilyl)erythromycin And methyliodide in an organic solvent in the presence of a base at a temperature of 0 to 10°C.

8. The method according to p. 7, where the organic solvent is a mixture of tetrahydrofuran and dimethyl sulfoxide, and the base depict the .2, where the stage of removal of the protective groups and the oxime group transformation of 9-O-tropological 2’,4’-O-bis(trimethylsilyl)-6-O-methylerythromycin And carried out by treatment of this compound with formic acid and sodium bisulfite in aqueous alcoholic solution at temperatures from room temperature up to the boiling point of the used solvent.

10. The method according to p. 1, where the mixture used in stage (a) contains water in an amount of 3 to 15 equivalents relative to the amount of clarithromycin.

11. The method according to p. 1, where miscible with water, the organic solvent is an acetone, ethanol, isopropanol or a mixture thereof.

12. The method according to p. 1, where methansulfonate acid is used in amount of from 0.9 to 1.1 equivalents relative to the amount of clarithromycin.

13. The method according to p. 1, where the mixture used in stage (b), consists of mixing with water, an organic solvent and water used in a volume ratio of 30:70 to 70:30.

14. The method according to p. 1, where the stage of neutralization (b) is carried out at a pH value of 9 to 12.

15. Trihydrate nelfinavir clarithromycin of formula (II)

16. 9-About-triperoxide derivative of erythromycin And formula (III)

where is item, if1represents methyl, R2represents a trimethylsilyl.

 

Same patents:

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

The invention relates to a derivative of 9-O-benzodithiophene erythromycin And formula (III), where Y1and Y2represent hydrogen atoms or trimethylsilyl group, or its crystalline MES, which are used as intermediate compounds for the synthesis of clarithromycin

The invention relates to an improved process for the preparation of the hydrochloride of the oxime erythromycin A (I)

The invention relates to a derivative of erythromycin General formula (II), (III), (IV) and (V), where R is a substituted C1-C10-alkyl, C3alkenyl,3-quinil, etc
The invention relates to the production of antibiotics, namely the technology of water-soluble salts of erythromycin, erythromycin phosphate

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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