Derived class oleandomitsina and method of production thereof

 

(57) Abstract:

The present invention relates to new compounds of the class of antibiotic is a macrolide oleandomycin General formula (I)

where R1individually represents a group - CH2CH3, a group of the formula (II), together with R2represents a group of formula (III) or together with R4represents a group of formula (IV) or a group of the formula (V)

R2together with R3represents a ketone or together with R1represents a group of formula (III)

R3individually represents a group HE or together with R2represents a ketone,

R4individually represents a methyl group or, together with R1represents a group of formula (IV) or a group of the formula (V)

R5separately represents hydrogen or benzyloxycarbonyl group

R6separately represents hydrogen, a methyl group or benzyloxycarbonyl group

and their pharmaceutically acceptable salts of inorganic or organic acids, as well as the way they are received. These compounds are intermediates for obtaining structural homologues chimeric oleanda the sky's the result - getting a new derived class oleandomitsina used in the production of antibiotics. 2 N. and 10 C.p. f-crystals.

The invention relates to new compounds of the class of antibiotic is a macrolide oleandomycin, to intermediate compounds for their production, to a method of production thereof, and their pharmaceutically acceptable additive salts of inorganic or organic acids.

The prior art.

Oleandomitsin is an antibiotic of the macrolide (U.S. patent No. 2757123), with a spectrum of activity similar to the spectrum of activity of erythromycin A. the Structure of oleandomycin characterized 14-membered Laktionova ring with geography in the C-9 position, saharacasino in 5-position and suhariyanto in the C-3 position, and the three groups HE. It differs from other polyoxometalates ekzoticheskim epoxy ring at C-8-atom. Early studies (JACS 82, 3225-3227, 1960; JOC 51, 5397-5400, 1986) showed his exceptional sensitivity both in acid and in alkaline medium. In an acid environment-8-epoxide opens, split oleanders and a narrowing aliceooa rings. Action base causes dehydration of H-10 and HE was 11 with the formation of C-10/C-11 double SV is.

It is known that such transformations occurring in the erythromycin And groups HE successfully inhibited their O-methylation (Watanable Y. and al., U.S. patent 4331803, 5/1982). As a result of reactions erythromycin And benzyloxycarbonylamino and subsequent methylation of the obtained derivatives of 2'-Oh,3'-N-bis(benzyloxycarbonyl), after removal of the protective groups and N-methylation are obtained, in addition to the 6-O-methylerythromycin (Clarithromycin), a significant number 11-O-methylerythromycin and polyamidine analogues (Morimo S. et al., J. Antibiotics, 1984, 37, 1987). Clarithromycin is significantly more resistant to acid than erythromycin A, and shows increased activity against strains of gram-positive bacteria in vitro (Kirst, H. A. et al., Antimicrobial Agents and Chemother., 1989, 1419). Like was also synthesized a number of O-methyl derivatives of azithromycin (Kobrehel G. et al, U.S. patent No. 5250518, 5/1993). Attempts were made to inhibit the formation of neaktivnogo of anhydroerythromycin O-methylation of the C-11-hydroxyl group, retroaldol fragmentation, dehydration and isomerization, which resulted in the receipt number is still not solved linear and cyclic derivatives oleandomitsina, which can serve as intermediates who's involves the reaction of oleandomitsina with benzyloxycarbonylamino obtaining 2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin, reaction with methyliodide in the presence of sodium hydride, removing the protective groups at positions 2' and 3' and the recovery of 3'-N-methylation.

Derivatives oleandomitsina in accordance with the present invention and their pharmaceutically acceptable additive salts of inorganic or organic acids, methods and intermediate compounds for their receipt is not disclosed in the prior art in this field.

Description of the invention with examples.

New derivatives of oleandomycin General formula (I)

where R1individually represents a group-CH2CH3, a group of the formula (II), together with R2represents a group of formula (III) or together with R4represents a group of formula (IV) or a group of the formula (V).

R2together with R3represents a ketone or together with R1represents a group of formula (III)

R3individually represents a group HE or together with R2represents a ketone,

R4individually represents a methyl group or, together with R1represents a group of formula (IV) or a group of the formula (V)

R5separately represents hydrogen or benzyloxycarbonyl group

and their pharmaceutically acceptable additive salts of inorganic or organic acids obtained as follows.

Stage 1:

Reaction oleandomitsina formula (VI) with benzyloxycarbonylamino in the presence of bases, preferably in the presence of sodium bicarbonate, in a solvent which is inert in the reaction mixture, preferably benzene or toluene, get 2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin General formula (I), where R1together with R4represents a group of formula (IV), R2together with R3represent ketone and R5and R6are the same and is benzyloxycarbonyloxy group.

Stage 2:

The reaction of 2'-Oh,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin with stradey 1 with 1,3-3,25 equivalents of the corresponding meteorologi agent, preferably under the conditions, and 1,1-3,75 equivalents of the appropriate base, preferably sodium hydride, at temperatures from-15C to room temperature, preferably at 0-5C, in a suitable aprotic solvent or solvent mixture, preferably DMSO-THF (DMSO-THF = 1:1, and the separation in the column of silica gel in the system toluene-ethyl acetate (SUB>CH3,

R2together with R3represents a ketone,

R4represents a methyl group and R5and R6are the same and represent benzyloxycarbonyloxy group

compound 2B General formula (I), where R1together with R4represents a group of formula (V)

R2together with R3represents the ketone and R5and R6are the same and represent benzyloxycarbonyloxy group

compound 2C General formula (I), where R1individually represents a group of formula (II), R2together with R3represents a ketone, R4represents a methyl group and R5and R6are the same and represent benzyloxycarbonyloxy group.

The relative ratio of chromatographically homogeneous product depends on equimolar relationship reagents.

Stage 3:

Each of the derived oleandomycin from stage 2 separately subjected to a hydrogenolysis reaction to remove the protective benzyloxycarbonyl groups in positions 2' and 3' in accordance with the method of E. N. Flynn et al. (Journal of American Chemical Society, 77, 3104, 1950). The hydrogenolysis is carried out in a solution of lower alcohol, preferably is rising accordingly

in case 2A compounds 3A General formula (I), where R1-R4have the meanings given for compounds 2A, and R5and R6are the same and represent hydrogen, and

in case 2B compounds 3B General formula (I), where R1-R4have the meanings given for compounds 2B, and R5and R6are the same and represent hydrogen, and

in the case of 2C, compound 3C General formula (I), where R1together with R2represents a group of formula (III), R3represents a group HE, R4represents a methyl group and R5and R6are the same and represent hydrogen.

Stage 4:

Each of the 3'-N-deletelink derived oleandomycin from the stage 3 is subjected to reductive N-methylation at position 3' 1-6,2 equivalents of formaldehyde (36%) in the presence of 1-4,2 equivalents of formic acid (98-100%) or other source of hydrogen in a solvent which is inert in the reaction mixture, such as halogenated hydrocarbons, lower alcohols or lower ketones, preferably chloroform, at the boiling temperature of the reaction mixture with obtaining respectively

in the case of 3A compounds 4A General formula (I), where Rpossessing a methyl group,

in case 3B compounds 4B General formula (I), where R1-R4have the meanings given for compounds 2B, R5is hydrogen and R6represents a methyl group, and

in the case of 3C compound 4C General formula (I), where R1-R4have the meanings given for compounds 2C, R5is hydrogen and R6represents a methyl group.

Group of formula (II), (III) and (V) shown without spatial orientation relationships and determine all combinations of orientation relations to include all possible stereoconfiguration, i.e. epimeres.

Pharmaceutically acceptable additive salts, which are also the object of the present invention, is produced by interaction of new derivatives oleandomitsina General formula (I), at least equimolar amounts of the corresponding inorganic or organic acid, such as hydrochloric, itestosterone, sulfuric, phosphoric, acetic, propionic, triperoxonane, malic, citric, stearic, succinic, Atlanterra, methansulfonate, benzolsulfonat, p-toluensulfonate, laurylsulphate acid, in a solvent which is inert in the reaction mixture. Additi Aut filtering, deposition by nerastvorimaya (precipitators) or by evaporation of the solvents, the most common way lyophilization.

The way to obtain new derivatives oleandomitsina is illustrated by the following non-limiting examples.

Example 1.

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin

To a solution of oleandomycin (50,98 g, 0,0741 mol) in benzene (385 ml) was added Panso3(226,74 g; 2,6990 mol) and the reaction mixture was heated under stirring to the boiling temperature (55-60°C). For 4 hours under stirring was added dropwise 95% benzyloxycarbonylamino (312 ml; 354,20 g; 2,0762 mol). The reaction mixture was stirred for another 24 hours at the same temperature and kept at room temperature for 42 hours. After filtration the residue was washed with benzene (75 ml) and Bentley solution three times was extracted with 100 ml of 0.25 N. Hcl and once with 100 ml of water. Bentley solution was dried over CaCl2, filtered and evaporated under reduced pressure to obtain a viscous oily residue (306,4 g) which was purified by chromatography at low pressure in a column with silica gel 60 (230-400 mesh ASTM mesh). In a column of silica gel (500 g) under nitrogen pressure 0,5105PA obtained on (1400 ml) and then using the system methylene chloride-methanol (95:5) (1000 ml) and evaporation of the fractions, containing chromatographically homogeneous specified in the title product was obtained 2'-Oh,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin (19,77 g) having the following physical-chemical constants:

EI-MS m/z 943,

TLC, methylene chloride-methanol (95:5) Rf 0,397,

Toluene-ethyl acetate, 1:1 Rf 0,420.

(IR) (KBr), cm-1: 3480, 2980, 2940, 1755, 1710, 1460, 1385, 1325, 1295, 1255, 1115, 1060, 1005, 990, 760, 700.

1H Yarm (300 MHz, Dl3) 7.35-7.28 (Ph), 5.11, 5.09 (CH2-Ph), 5.58 (H-13), 4.95 (H-1"), 4.66 (H-2'), 4.49 (H-1"), 4.41 (H-3'), 3.80 (H-11), 3.70 (H-5"), 3.46 (H-3"), 3.40 (3"-och3), 3.40 (H-5), 3.15 (H-4"), 3.00 (H-10), 3.00 (H-8A), 2.85 (H-8b), 2.83 (H-2), 2.80 (3'-NSN3), 2.35 (H-2"), 2.24 (H-7a), 1.73 (H-7b), 1.69 (H-6), 1.69 (H-4 h), 1.65 (H-4), 1.62 (H-12), 1.53 (H-2"b), 1.31 (5"-CH3), 1.26 (13-CH3), 1.22 (5'-CH3), 1.20 (2-CH3), 1.03 (6-CH3), 1.03 (10-CH3), 0.89 (4-CH3), 0.86 (12-CH3).

13With Yarm (75 MHz, Dl3) : 214.2 (C-9), 176.4 (C-1), 156.4, 156.0 (CCA), 154.4, 154.3 (NCO), 136.6 (OPh), 134.9 (NPh), 128.5-127.6 (Ph), 101.8 (C-1'), 99.0 (C-1"), 86.1 (C-5), 80.1 (C-3), 77.6 (C-3'), 75.8 (C-4"), 74.6 (C-2'), 70.2 (C-13), 69.2 (C-5'), 68.7 (C-11), 68.5 (-5"), 69.6, 69.5, 67.1, 66.9 (CH2Ph), 61.9 (C-8), 56.2 (3"-och3), 54.7 (C-3'), 50.2 (8-CH2), 44.5 (C-10), 44.3 (C-2), 42.2 (C-4), 41.4 (C-12), 35.4 (C-4), 33.8 (C-6), 33.6 (C-2"), 30.0 (C-7), 28.9 (3'-N3), 20.4 (5'-CH3), 18.1 (13-CH3), 17.6 (5"-CH3), 9.0 (4-CH3), 8.5 (12-CH3

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-dimethylamylamine (2B),

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demethyl-1-methoxy-10,11-anhydrous-1,13-SECO-oleandomitsin (2C).

To a solution of 2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin (6,00 g, 6.4 mmol) from example 1 in a mixture of dimethylsulfoxide-tetrahydrofuran (1:1,48 ml), cooled to 0-5°C. for 1 hour and successively added methyliodide (1,32 ml; of 20.7 mmol), diluted with a mixture of dimethylsulfoxide-tetrahydrofuran (1:1,12 ml) and 60% sodium hydride in mineral oil (0,76 g; 17.5 mmol). The reaction mixture was stirred at the same temperature for 2 hours. The reaction was stopped by the addition of triethylamine (10 ml), the reaction mixture was stirred for 10 minutes, was added a saturated solution of NaCl (80 ml) was stirred for another 10 minutes and was filtered inorganic part. The filtrate was extracted with ethyl acetate (80 ml), the organic layer twice washed with a saturated NaCl solution (80 ml) and dried over K2CO3. After filtration and evaporation under reduced pressure was obtained a yellowish amorphous precipitate (are 5.36 g). By column chromatography with silica gel using toluene-ethyl acetate (1:1) from the reaction mixture (2,82 g) was isolated chromacake homogeneous compound 2C (0.39 g), characterized by the following physico-chemical constants.

2A

TLC, methylene chloride-methanol (95:5) Rf 0,587,

toluene-ethyl acetate (1:1) Rf 0,687.

(IR) (KBR)cm-1: 3480, 2980, 2940, 1750, 1710, 1455, 1385, 1335, 1295, 1260, 1165, 1110, 1055, 1005, 830, 790, 760, 700.

1H NMR (300 MHz, Dl3) : 7.35-7.27 (Ph), 5.12, 5.09 (CH2-Ph), 4.89 (H-1"), 4.64 (H-2'), 4.49 (H-1'), 4.46 (H-3'), 3.90 (H-3), 3.70 (1-cos3), 3.70 (H-5"), 3.61 (H-5'), 3.45 (H-3"), 3.41 (H-5), 3.40 (3"-OCH3), 3.12 (N-4"), 2.85 (3'-N3), 2.79 (N-2), 2.76 (H-8A), 2.74 (H-8b), 2.56 (H-7a), 2.39 (H-10A), 2.34 (H-10b), 2.27 (H-2"), 1.90 (H-6), 1.73 (H-4), 1.70 (H-4 h), 1.61 (H-4'b), 1.46 (H-2"b), 1.22 (5'-CH3), 1.21 (5"-CH3), 1.18 (2-CH3), 1.16 (H-7b), 1.03 (6-CH3), 1.03 (10-CH3), 0.90 (4-CH3).

13With NMR (75 MHz, Dl3) : 209.5 (C-9), 175.2 (C-1), 156.1, 155.7 (CCA), 154.2, 154.1 (NCO), 136.3 (OPh), 134.9 (NPh), 129.2-127.3 (Ph), 100.9 (C-11), 97.8 (C-1"), 82.9 (C-5), 79.7 (C-3), 77.8 (C-3'), 75.5 (C-4"), 74.3 (C-2'), 68.2 (C-5'), 68.2 (-5"), 69.3, 69.1, 67.1, 66.9 (CH2-Ph), 62.1 (C-8), 56.1 (3"-och3), 54.5 (C-3'), 51.5 (1-COS3), 49.9 (8-CH2), 42.0 (C-2), 39.4 (C-4), 35.9 (C-4'), 33.9 (C-2"), 32.4 (C-6), 31.7 (C-7), 29.1 (10-CH3), 28.4 (3'-N3), 20.3 (5'-CH3), 17.6 (6-CH3), 17.4 (5"-CH3), 11.9 (2-CH3), 9.7 (4-CH3), 7.1 (10-CH3).

2V

TLC, methylene chloride-methanol (95:5), Rf 0,447,

toluene-ethyl acetate (1:1), Rf 0,520,

3) : 7.38-7.27 (Ph), 5.13, 5.08 (CH2-Ph), 4.88 (H-13), 4.88 (H-1"), 4.66 (H-2'), 4.47 (H-3'), 4.41 (H-1'), 3.85 (H-11), 3.68 (H-5"), 3.66 (H-3), 3.62 (H-5'), 3.43 (N-3"), 3.40 (3"-och3), 3.33 (H-5), 3.26 (H-10), 3.13 (H-4"), 2.83 (H-8A), 2.83 (H-8b), 2.81 (3'-N3), 2.67 (N-2), 2.64 (H-7a), 2.34 (H-2"), 1.76 (H-6), 1.72 (H-12), 1.70 (H-4 h), 1.70, (H-4), 1.62 (H-4'b), 1.50 (H-2"b), 1.32 (H-7b), 1.28 (13-CH3), 1.27 (5"-CH3), 1.22 (5'-CH3), 1.18 (2-CH3), 1.12 (6-CH3), 1.06 (10-CH3), 1.03 (12-CH3), 0.96 (4-CH3).

13With NMR (75 MHz, Dl3) : 211.3 (C-9), 174.9 (C-1), 156.5, 156.1 (CCA), 154.5, 154.4 (NCO), 136.6 (OPh), 135.0 (NPh), 128.5-127.6 (Ph), 101.6 (C-1'), 98.8 (C-1"), 83.9 (C-5), 79.8 (C-3), 77.7 (C-3'), 75.8 (C-4"), 74.6 (C-2'), 73.2 (C-13), 70.1 (C-11), 68.5 (C-5"), 68.3 (-5'), 69.6, 69,4, 67,0, 66.9 (CH2-Ph), 61.5 (C-8), 56.2 (3"-och3), 54.6 (C-3'), 51.2 (8-CH2), 44.6 (C-2), 43.3 (C-4), 42.4 (C-10), 40.5 (C-12), 35.5 (C-4'), 33.7 (C-2"), 32.0 (C-6), 30.7 (C-7), 28.5 (3'-N3), 20.4 (5'-CH3), 19.8 (6-CH3), 17.5 (5"-CH3), 15.2 (13-CH3), 13.6 (2-CH3), 10.5 (12-CH3), 10.2 (10-CH3), 9.2 (4-CH3).

2C

TLC, methylene chloride-methanol (95:5), Rf 0,420,

toluene-ethyl acetate (1:1), Rf 0,360,

(IR) (KBR)cm-1: 3460, 2970, 2930, 1740, 1690, 1450, 1380, 1330, 1290, 1250, 1160, 1110, 1050, 1000, 785, 755, 695, 665.

1H NMR (300 MHz, Dl3) : 7.34-7.20 (Ph), 6.74 (H-11), 5.10, 5.09 (CH2-Ph), 4.84 (H-1"), 4.64 (H-2'), 4.51 (H-1'), 4.43 (H-3'), 3.94 (H-3), 3.84 (H-13), 3.72 (H-5"), 3.58 (N-5'), 3.44 (1-2.19 (H-2"), 1.84 (10-CH3), 1.78 (H-4), 1.74 (H-4 h), 1.69 (H-6), 1.39 (H-2"b), 1.24 (5"-CH3), 1.22 (H-7b), 1.22 (13-CH3), 1.22 (5'-CH3), 1.08 (12-CH3), 1.07 (2-CH3), 1.00 (6-CH3), 0.82 (4-CH3).

13With NMR (75 MHz, Dl3) : 199.0 (C-9), 175.7 (C-1), 156.3, 156.0 (CCA), 154.6, 154.4 (NCO), 147.7 (C-11), 136.5 (OPh), 135.2 (NPh), 134.1 (C-10), 128.7-127.4 (Ph), 101.0 (C-1'), 97.4 (C-1'), 82.6 (C-5), 79.6 (C-3), 78.0 (C-3"), 75.8 (C-4"), 74.3 (C-2'), 70.3 (C-13), 68.6 (C-5'), 68.3 (C-5"), 69.6, 69.3, 67.1, 66.9 (CH3-Ph), 62.0 (C-8), 56.1 (3"-och3), 55.1 (C-3'), 51.7 (1-COS3), 50.0 (8-CH2), 41.0 (C-12), 40.3 (C-2), 38.6 (C-4), 37.0 (C-7), 35.4 (C-4'), 33.9 (C-2"), 33.1 (C-6), 28.9 (3'-N3), 20.9 (5'-CH3), 20.7 (13-CH3), 17.5 (5"-CH3), 16.8 (6-CH3), 14.0 (2-CH3), 11. 5 (10-CH3), 10.1 (12-CH3), 9.4 (4-CH3).

Example 2.

Method C.

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demethyl-11,12,13-trinor-1-methoxy-10,11-SECO-oleandomitsin (2A)

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demethyl-1-methoxy-10,11-anhydrous-1,13-SECO-oleandomitsin (2C)

To a solution of 2'-Oh,3'-N-bis(benzyloxycarbonyl)-3'-N-demetilklindamiqin (6,00 g, 6.4 mmol) from example 1 in a mixture of dimethylsulfoxide-tetrahydrofuran (1:1,12 ml), cooled to 0-5C, within 1 hour consistently added methyliodide (1,32 ml; of 20.7 mmol), diluted with a mixture of dimethylsulfoxide - tetrahydrofuran (1:1,12 ml) the ur for 2 hours. The reaction was stopped by the addition of triethylamine (10 ml), the reaction mixture was stirred for 10 minutes, was added a saturated solution of NaCl (80 ml) was stirred for another 10 minutes and was filtered inorganic part. The filtrate was extracted with ethyl acetate (80 ml), the organic layer twice washed with a saturated NaCl solution (80 ml) and dried over K2CO3. After filtration and evaporation under reduced pressure was obtained a yellowish amorphous precipitate (5,90 g). By column chromatography with silica gel using toluene-acetate (1:1) from the reaction mixture (2,95 g) was isolated chromatographically homogeneous compound 2A (0.12 g) and chromatographically homogeneous compound 2C (0.40 g), characterized by physico-chemical constants given in example 2, method A.

Example 2.

Method C.

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demethyl-11,12,13-trinor-1-methoxy-10,11-SECO-oleandomitsin (2A)

2'-O,3'-N-bis(benzyloxycarbonyl)-3'-N-demethyl-EPI-oleandomitsin (2V)

To a solution of 2'-Oh,3'-N-bis(benzyloxycarbonyl)-3'-N-demetillo-oleandomycin (6,00 g, 6.4 mmol) from example 1 in a mixture of dimethylsulfoxide-tetrahydrofuran (1:1,48 ml), cooled to 0-5C, within 1 hour consistently added m is in mineral oil (0,30 g; 6.8 mmol). The reaction mixture was stirred at the same temperature for 2 hours. The reaction was stopped by the addition of triethylamine (10 ml), the reaction mixture was stirred for 10 minutes, was added a saturated solution of NaCl (80 ml) was stirred for another 10 minutes and was filtered inorganic part. The filtrate was extracted with ethyl acetate (80 ml), the organic layer twice washed with a saturated NaCl solution (80 ml) and dried over K2CO3. After filtration and evaporation under reduced pressure was obtained a yellowish amorphous precipitate (5.59 in). By column chromatography with silica gel using toluene-ethyl acetate (1:1) from the reaction mixture (2,80 g) was isolated chromatographically homogeneous compound 2A (0,44 g) and chromatographically homogeneous compound 2B (0.66 g), characterized by physico-chemical constants given in example 2, method A.

Example 3.

3'-N-demethyl-11,12,13-trinor-1-methoxy-10,11-SECO-oleandomitsin (3A)

The product 2A (2.65 g, 3 mmol) was dissolved in ethanol (42 ml) using a buffer with a pH of 5 (0,19 ml SPLA, 0,30 g NaOAc and 10 ml of water) was adjusted pH to 6.8, was added 10% Pd/C (0.28 g) and the reaction mixture was first made with stirring for 3.5 hours in an autoclave at diflucane viscous syrup, added l3(50 ml) and water (50 ml) using 20% NaOH regulate the pH of the mixture to 9.0, the layers were separated and the aqueous extract more than three times were extracted l3(50 ml). The combined organic extracts were dried over K2CO3was filtered , evaporated under reduced pressure, optionally purified by column chromatography with silica gel using chloroform - methanol - concentrated ammonia (60:10:1), to receive specified in the header of the product (1.45 g) having the following physical-chemical constants:

EI-MS m/z 604,

TLC, chloroform - methanol - concentrated ammonia (60:10:1), Rf 0.602,

methylene chloride - methanol - concentrated ammonia (90:9:1.5), Rf 0.358.

(IR) (KBR) cm-1: 3310, 2970, 2930, 1730, 1715, 1465, 1455, 1380, 1260, 1195, 1155, 1070, 1045, 1005,985,900,755,665.

1H NMR (300 MHz, Dl3) : 4.90 (H-1"), 4.27 (H-1'), 3.99 (H-3), 3.74 (H-5"), 3.70 (1-COS3), 3.55 (H-5'), 3.46 (H-5), 3.42 (H-3"), 3.40 (3"-OCH3), 3.19 (H-2'), 3.17 (H-4"), 2.81 (N-2), 2.77 (H-8A), 2.74 (H-8b), 2.67 (H-7a), 2.52 (H-3'), 2.41 (H-10A), 2.40 (3'-N3), 2.35 (H-10b), 2.29 (H-2"), 2.05 (H-6), 1.93 (N-4 h), 1.87 (H-4), 1.49 (H-2"b), 1.28 (5"-CH3), 1.21 (2-CH3), 1.20 (H-4'b), 1.20 (5'-CH3), 1.10 (H-7b), 1.04 (4-CH3), 1.02 (6-CH3), 1.02 (10-CH3).

13With NMR (75 MHz, Dl33), 51.4 (1-COS3), 49.8 (8-CH2), 42.0 (C-2), 39.1 (C-4), 36.6 (C-4'), 33.9 (-2"), 32.7 (3'-N3), 32.6 (C-7), 32.3 (C-6), 29.0 (10-CH2), 20.6 (5'-CH3), 17.2 (5"-CH3), 17.0 (6-CH3), 11.7 (2-CH3), 10.3 (4-CH3), 6.9 (10-CH3).

Example 4.

3'-N-demethyl-EPI-oleandomitsin (3V)

Product 2B (1.42 g, 1.5 mmol) was dissolved in ethanol (23 ml) using a buffer with a pH of 5 (0,19 ml SPLA, 0,30 g NaOAc and 10 ml of water), regulating pH to 6.8, was added 10% Pd/C (0.15 g) and the reaction mixture was first made with stirring for 4.5 hours in an autoclave at a hydrogen pressure of 105PA at room temperature. The selection was carried out as in example 3. After evaporation under reduced pressure the product is optionally purified by column chromatography with silica gel using chloroform-methanol-concentrated ammonia (60:10:1), to receive specified in the header of the product (0,99 g) having the following physical-chemical constants:

EI-MS m/z 674,

TLC, chloroform - methanol - concentrated ammonia

(60:10:1), Rf 0.370, methylene chloride - methanol - concentrated ammonia

(90:9:1.5) Rf 0.170.

(IR) (KBr) cm-1: 3450, 2980, 2940, 2900, 1730, 1715, 1465, 1455, 1385, 1255, 1190, 1155, 1070, 1050, 1000, 875, 755, 670.

1, 3.23 (H-10), 3.17 (H-2'), 3.15 (H-4"), 2.88 (H-8A), 2.88 (H-8b), 2.77 (H-2), 2.53 (N-3'), 2.41 (3'-N3), 2.34 (H-2"), 2.21 (H-7a), 1.95 (N-4 h), 1.94 (H-6), 1.85 (H-7b), 1.70 (H-4), 1.53 (H-12), 1.51 (H-2"b). 1.30 (5"-CH3), 1.27 (13-CH3), 1.21 (5'-CH3), 1.20 (2-CH3), 1.18 (H-4'b), 1.13 (6-CH3), 1.10 (12-CH3), 1.09 (10-CH3), 1.09 (4-CH3).

13With NMR (75 MHz, Dl3) : 212.2 (C-9), 174.5 (C-1), 102.9 (C-1'), 99.9 (C-1"), 81.5 (C-3), 81.1 (C-5), 77.7 (C-3'), 75.6 (C-4"), 73.9 (C-2'), 71.1 (C-13), 70.0 (C-11), 68.6 (C-5"), 68.5 (C-5'), 61.2 (C-8), 59.6 (-3'), 56.3 (3"-OCH3), 49.9 (8-CH2), 44.6 (C-2), 42.6 (C-12), 41.8 (C-10), 40.5 (C-4), 36.9 (C-4'), 33.9 (-2"), 32.9 (3'-N3), 31.7 (C-7), 30.6 (C-6), 20.7 (5'-CH3), 20.2 (6-CH3), 17.6 (5"-CH3), 16.7 (13-CH3), 14.8 (2-CH3), 10.1 (12-CH3), 9.9 (4-CH3), 9.2 (10-CH3).

Example 5.

3'-N-demethyl-1-methoxy-1,13-SECO-oleandomitsin-9-13-Hemi-ketal (3C)

Product 2C (1.28 g, 1.3 mmol) was dissolved in ethanol (21 ml), brought the pH to 6.8 using a buffer with a pH of 5 (0,19 ml SPLA, 0,30 g NaOAc and 10 ml of water) was added 10% Pd/C (0.18 g) and the reaction mixture was first made with stirring for 6 hours in an autoclave at a hydrogen pressure of 105 PA at room temperature. The selection was carried out as in example 3. After evaporation under reduced pressure the product is optionally purified by chromatography in a column with silicagel the title product (0,81 g) having the following physical-chemical constants:

EI-MS m/z 690,

TLC, chloroform - methanol - concentrated ammonia (60:10:1), Rf 0.556,

methylene chloride - methanol - concentrated ammonia (90:9:1.5), Rf 0.302. (IR) (KBR) cm-1: 3470, 2980, 2940, 2900, 1735, 1465, 1455, 1385, 1265, 1205, 1160, 1075, 1040, 1000, 900, 760, 670.

1H NMR (300 MHz, Dl3) : 4.84 (H-1"), 4.30 (H-1'), 4.15 (H-13), 4.03 (H-3), 3.76 (H-5"), 3.71 (1-COS3), 3.56 (H-5'), 3.45 (H-3"), 3.42 (H-5), 3.39 (3"-OCH3), 3.18 (H-2'), 3.14 (H-4"), 2.84 (H-8A), 2.79 (N-2), 2.63 (H-8b), 2.54 (H-3'), 2.44 (H-7a), 2.41 (3'-N3), 2.26 (H-2"), 2.10 (H-10), 1.96 (N-6), 1.94 (N-4 h), 1.92 (H-4), 1.85 (H-11a), 1.66 (H-12), 1.47 (H-2"b), 1.40 (H-11b), 1.36 (H-7b), 1.28 (5"-CH3), 1.22 (5'-CH3), 1.19 (H-4'b), 1.16 (2-CH3), 1.04 (6-CH3), 1.00 (13-CH3), 0. 98 (12-CH3), 0.98 (4-CH3), 0.81 (10-CH3).

13NMR (75 MHz, DCl3) : 175.8 (C-1), 103.7 (C-1'), 98.1 (C-1"), 97.4 (C-9), 82.7 (C-5), 80.6 (C-3), 78.0 (C-3'), 75.6 (C-4"), 74.0 (C-2'), 68.7 (C-5'), 68.5 (C-5"), 66.9 (C-13), 60.5 (C-8), 60.1 (-3'), 56.2 (3"-OCH3), 51.7 (1-COS3), 49.5 (8-CH3), 41.7 (C-2), 38.5 (C-4), 36.9 (C-4'), 35.5 (C-11), 34.0 (-2"), 32. 9 (3'-N3), 32.0 (C-12), AND 31.7 (C-6), 30.8 (C-7), 27.4 (C-10), 20.9 (5'-CH3), 18.3 (4-CH3), 18.0 (13-CH3), 17. 4 (5"-CH3), 15.9 (10-CH3), 11.6 (12-CH3), 11.0 (2-CH3), 10.5 (6-CH3).

Example 6.

11,12,13-trinor-1-methoxy-10,11-SECO-oleandomitsin (4A).

To a solution of 3'-N-demethyl-11,12,13-trinor-1-8.5 mmol) and 98 - 100% formic acid (0,217 ml, 5.8 mmol). The reaction mixture was stirred for 3.5 hours while boiling under reflux, cooled to room temperature, poured into water (60 ml) with 2n. NaOH brought the pH of the mixture to 9.0, the layers were separated and the aqueous layer was more than three times were extracted l3(30 ml). The combined organic extracts were dried over K2CO3was filtered , evaporated under reduced pressure, optionally purified in a column of silica gel using chloroform - methanol - concentrated ammonia (60:10:1), to receive specified in the header of the product (0.97 g) having the following physical-chemical constants:

EI-MS m/z 618,

TLC, chloroform - methanol - concentrated ammonia

(60:10:1) Rf 0.787,

methylene chloride - methanol - concentrated ammonia (90:9:1.5), Rf 0.575.

(IR) (KBR) cm-1: 3450, 2970, 2930, 1735, 1715, 1460, 1455, 1380, 1260, 1195, 1160, 1075, 1045, 1000, 795, 755.

1H NMR (300 MHz, Dl3) : 4.92 (H-1"), 4.27 (H-1'), 4.00 (N-3), 3.77 (H-5"), 3.69 (1-COS3), 3.48 (H-5'), 3.46 (H-3"), 3.41 (H-5), 3.40 (3"-OCH3), 3.23 (H-2'), 3.14 (H-4"), 2.83 (H-2), 2.78 (H-8A), 2.75(H-8b), 2.66 (H-7a), 2.49 (H-3'), 2.43 (H-10A), 2.28 (3'-N(CH3)2), 2.37 (H-10b), 2.31 (H-2"), 2.04 (H-6), 1.88 (H-4), 1.65 (H-4 h), 1.48 (H-2"b), 1.29 (5"-CH3), 1.24 (H-4'b), the Mr (75 MHz, Dl3) : 209.9 (C-9), 175.6 (C-1), 104.0 (C-1'), 98.5 (C-1"), 83.1 (C-5), 80.5 (C-3), 77.9 (C-3"), 75.7 (C-4"), 70.1 (C-2'), 68.9 (C-5'), 68.2 (C-5"), 65.2 (C-3'), 62.1 (C-8), 56.0 (3"-OCH3), 51.4 (1-COS3), 49.9 (8-CH2), 42.6 (C-2), 40.0 (3'-N(CH3)2), 39.6 (C-4), 33.9 (C-2"), 31.9 (C-6), 31.8 (C-7), 29.0 (10-CH2), 28.4 (-4'), 20.8 (5'-CH3), 17.5 (6-CH3), 17. 2 (5"-CH3), 12.7 (2-CH3), 10.1 (4-CH3), 7.0 (10-CH3).

Example 7.

EPI-Oleandomitsin (4V)

To a solution of 3'-N-demethyl-EPI-oleandomitsina from example 4 (1.12 g; 1.7 mmol) in l3(75 ml) was added 36% formaldehyde (0,291 ml, 10.5 mmol) and 98 - 100% formic acid (0,267 ml, 7.1 mmol). The reaction mixture was stirred for 7 hours while boiling under reflux. The selection was carried out as in example 6. After evaporation under reduced pressure the product is optionally purified in a column of silica gel using methylene chloride - methanol - concentrated ammonia (90:9:1.5), in thus received is specified in the header of the product (1,11 g) having the following physical-chemical constants:

EI-MS m/z 688,

TLC, chloroform - methanol - concentrated ammonia

(60:10:1), Rf 0.667

methylene chloride - methanol - concentrated ammonia

(90:9:1.5), Rf 0.415.

(IR) (rl3) : 4.96 (H-13), 4.88 (H-1"), 4.21 (H-1'), 3.83 (H-11), 3.74 (H-5"), 3.72 (H-3), 3.48 (H-5'), 3.46 (H-3"), 3.41 (3"-OCH3), 3.41 (H-5), 3.26 (H-10), 3.26 (H-2'), 3.15 (H-4"), 2.79 (H-8A), 2.79 (H-8b), 2.78 (N-2), 2.63 (H-7a), 2.55 (H-3'), 2.36 (H-2"), 2.33 (3'-N(CH3)2), 1.88 (H-6), 1.84 (H-4), 1.77 (H-12), 1.71 (N-4 a), 1.53 (H-7b), 1.51 (H-2"b), 1.29 (5"-CH3), 1.29 (13-CH3), 1.27 (H-4'b), 1.23 (2-CH3), 1.22 (5'-CH3), 1.17 (4-CH3), 1.15 (6-CH3), 1.07 (12-CH3), 1.06 (10-CH3).

13With NMR (600 MHz, Dl3) : 210.6 (C-9), 174.1 (C-1), 104.0 (C-1'), 99.8 (C-1"), 83.0 (C-5), 81.9 (C-3), 77.7 (C-3"), 75.7 (C-4"), 72.8 (C-13), 70.1 (C-2'), 69.4 (C-11), 68.9 (C-5'), 68.4 (C-5"), 65.1 (C-3'), 60.9 (C-8), 56.1 (3"-OCH3), 51.1 (8-CH2), 44.8 (C-2), 42.4 (C-10), 42.3 (C-4), 40.1 (C-12), 39.9 (3'-N(CH3)2), 33.9 (C-2"), 31.7 (C-7), 31.0 (C-6), 28.3 (-4'), 20.8 (5'-CH3), 19.2 (6-CH3), 17.2 (5"-CH3), 15.5 (13-CH3), 14.5 (2-CH3), 11.0 (12-CH3), 9.6 (4-CH3), 8.7 (10-CH3).

Example 8.

1-Methoxy-1,13-SECO-oleandomitsin-9,13-hemiketal (4C)

To a solution of 3'-N-demethyl-1-methoxy-1,13-SECO-oleandomitsin-9,13-hemiketal (1.19 g; 1.7 mmol) from example 5 in SNS3(80 ml) was added 36% formaldehyde (0,274 ml; 9.9 mmol) and 98-100% formic acid (0,252 ml, 6.7 mmol). The reaction mixture was stirred for 5 hours while boiling under reflux. The selection was carried out as in example 6. After in the istemi methylene chloride - methanol - concentrated ammonia (90:9:1.5), in thus received is specified in the header of the product (0.85 grams) with the following physical-chemical constants:

EI-MS m/z 704,

TLC, chloroform - methanol - concentrated ammonia (60:10:1), Rf 0.759,

methylene chloride - methanol - concentrated ammonia (90:9:1.5), Rf 0.509.

(IR) (KBr) cm-1: 3465, 2973, 2936, 2788, 1733, 1456, 1383, 1298, 1260, 1199, 1163, 1109, 1078, 1050, 1005, 987, 932, 895, 833, 755, 666.

1H NMR (500 MHz, Dl3) : 4,88 (H-1"), 4.29 (H-1'), 4.15 (H-13), 4.00 (N-3), 3.78 (N-5"), 3, 69 (1-OCH3), 3.49 (H-5'), 3.45 (H-3"), 3.41 (H-5), 3.40 (3"-OCH3), 3.27 (H-2'), 3.14 (H-4"), 2.83 (H-8A), 2.81 (N-2), 2.67 (H-8b), 2.52 (H-3'), 2.38 (H-7a), 2.30 (3'-N(CH3)2), 2.25 (H-2"), 2.12 (H-10), 1.87 (H-6), 1.85 (H-4), 1.82 (H-11a), 1.67 (H-4'a), 1.62 (H-12), 1.47 (H-7b), 1.44 (H-2"b), 1.37 (H-11b), 1.28 (H-4'b), 1.28 (5"-CH3), 1.23 (5'-CH3), 1.16 (2-CH3), 1.11 (6-CH3), 1.04 (4-CH3), 1.04 (13-CH3), 0.99 (12-CH3), 0.81 (10-CH3).

13With NMR (500 MHz, Dl3) : 175.7 (C-1), 104.2 (C-1'), 98.1 (C-1"), 97.4 (C-9), 83.0 (C-5), 80.6 (C-3), 78.0 (C-3'), 75.8 (C-4"), 70.3 (C-2'), 69.0 (C-5'), 68.3 (C-5"), 66.9 (C-13), 65.2 (C-3'), 60.5 (C-8), 56.1 (3"-OCH3), 51.6 (1-COS3), 49.6 (8-CH2), 42.0 (C-2), 40.1 (3'-N(CH3)2), 38.9 (C-4), 35.6 (C-11), 34.0 (C-2"), 32.1 (C-12), 31.3 (C-6), 30.0 (C-7), 28.8 (C-4'), 27.3 (C-10), 21.0 (5'-CH3), 18.3 (4-CH3), 18.2 (13-CH3), 17.4 (5"-CH3), 15.9 (10-what's 15-membered oleandomitsin-9a-azalides derived oleandomycin formula I, where R1individually represents-CH2CHC, R2and R3together represent ketogroup, R4individually is methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group, is carried out in accordance with the following reaction scheme:

C. Obtaining chimeric 14-membered oleandomitsin - 9a-azalides derived oleandomycin formula I, where R1individually represents-CH2CH3, R2and R3together represent ketogroup, R4individually is methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group, is carried out in accordance with the following reaction scheme:

Example 10.

Getting oleandomycin 14-membered 9-catasetinae and their subsequent transformation in 14 - and 15-membered oleandomitsin - 9a-azalides.

A. 14-membered derived oleandomycin WITHandgain from derivative oleandomycin formula I, where R1separately ecstasy methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group in accordance with the following reaction scheme:

Next, a 14-membered derived oleandomycin WITHasubjected to reaction disclosure rings deriving oleandomitsina formula I, where R1individually represents-CH2CH3or a group of formula (II), R" and R3together represent ketogroup, R4individually is methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group, by reaction first with benzyloxycarbonylamino and, further, with meteorous agent, preferably methiodide's 2.5-3.25 equiv.) in the presence of a base, preferably sodium hydride (2.5 to 3.25 equiv.) at a temperature of from -15°C. to room temperature, preferably at 0-5°C in an appropriate aprotic solvent or mixture of solvents, preferably DMSO:THF = 1:1.

Century 14-membered derived oleandomycin WITHbgain from derivative oleandomycin formula I, g, 4individually is methyl, R5separately represents hydrogen and R6separately represents hydrogen or methyl, in accordance with the following reaction scheme:

Like Ca14-membered derived oleandomycin WITHbsubjected to reaction disclosure rings deriving oleandomitsina formula I, where R1individually represents-CH2CH3or a group of formula (II), R2and R3together represent ketogroup, R4individually is methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group, by reaction first with benzyloxycarbonylamino and forth with meteorous agent, preferably methyliodide's 2.5-3.25 equiv.) in the presence of a base, preferably sodium hydride (2.5 to 3.25 equiv.) at a temperature of from -15°C. to room temperature, preferably at 0-5°C, in an appropriate aprotic solvent or mixture of solvents, preferably DMSO:THF = 1:1.

C. In accordance with methods similar to those described in a and b of example 10, 14-membered derived oleandomycin fo>together represent ketogroup, R4individually is methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group, is subjected to reaction disclosure. ring first with benzyloxycarbonylamino and forth with meteorous agent, preferably methyliodide's 2.5-3.25 equiv.) in the presence of a base, preferably sodium hydride (2.5 to 3.25 equiv.) at a temperature of from -15°C. to room temperature, preferably at 0-5°C, in an appropriate aprotic solvent or mixture of solvents, preferably DMSO:THF = 1:1, to obtain the derivative oleandomycin formula I, where R1individually represents-CH2CH3or a group of formula (II), R2and R3together represent ketogroup, R4individually is methyl, R5separately represents hydrogen or benzyloxycarbonyl group, and R6separately represents hydrogen, methyl or benzyloxycarbonyloxy group.

1. Derived class oleandomitsina General formula (I)

where R1individually represents a group-CH2CH3group V) or a group of the formula (V)

R2together with R3represents a ketone or together with R1represents a group of formula (III);

R3individually represents a group HE or together with R2represents a ketone;

R4individually represents a methyl group or, together with R1represents a group of formula (IV) or a group of the formula (V);

R5separately represents hydrogen or benzyloxycarbonyl group;

R6separately represents hydrogen, a methyl group or benzyloxycarbonyl group

and its pharmaceutically acceptable additive salts of inorganic or organic acids.

2. Connection on p. 1, where R1together with R4represents a group of formula (IV), R2together with R3represents the ketone and R5and R6are the same and represent benzyloxycarbonyloxy group.

3. Connection on p. 1, where R1represents a group-CH2CH3, R2together with R3represents a ketone, R4represents a methyl group and R5and R6are the same and represent benzyloxycarbonyloxy group.

4. With the hat ketone and R5and R6are the same and represent benzyloxycarbonyloxy group.

5. Connection on p. 1, where R1represents a group of formula (II), R2together with R3represents a ketone, R4represents a methyl group and R5and R6are the same and represent benzyloxycarbonyloxy group.

6. Connection on p. 1, where R1represents a group-CH2CH3, R2together with R3represents a ketone, R4represents a methyl group and R5and R6are the same and represent hydrogen.

7. Connection on p. 1, where R1together with R4represents a group of formula (V), R2together with R3represents the ketone and R5and R6are the same and represent hydrogen.

8. Connection on p. 1, where R1together with R2represents a group of formula (III), R3represents a group HE, R4represents a methyl group and R5and R6are the same and represent hydrogen.

9. Connection on p. 1, where R1represents a group-CH2CH3, R2together with R3represents a ketone, R4and R6are the same and represent marestella group of the formula (V), R2together with R3represents a ketone, R5is hydrogen and R6represents a methyl group.

11. Connection on p. 1, where R1together with R2represents a group of formula (III), R3represents a group HE, R4and R6are identical and represent a methyl group and R5represents hydrogen.

12. The method of obtaining compounds of General formula (I)

where R1individually represents a group-CH2CH3, a group of the formula (II), together with R2represents a group of formula (III) or together with R4represents a group of formula (IV) or a group of the formula (V);

R2together with R3represents a ketone or together with R1represents a group of formula (III);

R3individually represents a group HE or together with R2represents a ketone;

R4individually represents a methyl group or, together with R1represents a group of formula (IV) or a group of the formula (V);

R5separately represents hydrogen or benzyloxycarbonyl group;

R6separately represents hydrogen, methyl the inorganic or organic acids, characterized in that oleandomitsin formula (VI)

subjected to reaction with benzyloxycarbonylamino in the presence of a base, preferably sodium bicarbonate, in a solvent which is inert in the reaction mixture, preferably benzene or toluene, to obtain the 2'-0,3'-N-bis(benzyloxycarbonyl)-3'-N-dimethyloleylamine General formula (I), where R1together with R4represents a group of formula (IV), R2together with R3represents the ketone and R5and R6are the same and represent benzyloxycarbonyloxy group, which is then subjected to the action of the corresponding meteorologi agent, preferably under the conditions, in the presence of an appropriate base, preferably sodium hydride, at temperatures from-15C to room temperature, preferably at 0-5C, in a suitable aprotic solvent or mixture of solvents, preferably DMSO-THF=1:1, and the separation in the column of silica gel in the system toluene-ethyl acetate=1:1 to receive chromatographically homogeneous compounds 2A General formula (I), where R1represents a group-CH2CH3, R2together with R3represents a ketone, R4represents a methyl group and R5, the de R1together with R4represents a group of formula (V); R2together with R3represents the ketone and R5and R6are the same and represent benzyloxycarbonyloxy group, and compounds 2C General formula (I), where R1represents a group of formula (II), R2together with R3represents a ketone, R4represents a methyl group and R5and R6are the same and represent benzyloxycarbonyloxy group, each of them separately subjected to a hydrogenolysis reaction in the solution of lower alcohol, preferably in ethanol, in the presence of buffer NaOAc/HOAc (pH 5) with a catalyst such as palladium black or palladium on charcoal, at a hydrogen pressure of 105PA at room temperature with obtaining, respectively, in the case of 2A, compounds 3A General formula (I), where R1-R4have the meanings given for compounds 2A, and R5and R6are the same and represent hydrogen; in case 2B, compounds 3B General formula (I), where R1-R4have the meanings given for compounds 2B, and R5and R6are the same and represent hydrogen; in the case of 2C, compound 3C General formula (I), where R1together with R2is grouplets the same and represent hydrogen, each of them separately subjected to reductive N-methylation at position 3' 1-6,2 equivalents of formaldehyde (36%) in the presence of 1-4,2 equivalents of formic acid (98-100%) or other source of hydrogen in a solvent which is inert in the reaction mixture, such as halogenated hydrocarbons, lower alcohols or lower ketones, preferably chloroform, at the boiling temperature of the reaction mixture with obtaining, respectively, in the case of 3A, compound 4A General formula (I), where R1-R4have the meanings given for compounds 2A, R5is hydrogen and R6represents a methyl group; in the case of 3B, compound 4B General formula (I), where R1-R4have the meanings given for compounds 2B, R5is hydrogen and R6represents a methyl group; in the case of 3C, compounds 4C General formula (I), where R1-R4have the meanings given for compounds 3C, R5is hydrogen and R6represents a methyl group, which are then optionally subjected to reaction with inorganic or organic acids to produce their pharmaceutically acceptable additive salts.

 

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< / BR>
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50 cl, 10 dwg, 10 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for preparing a composition in form of particles, containing anhydrous crystalline 2-glucoside ascorbic acid, and can be used in pharmaceutical industry. Proposed method comprises allowing cyclomaltodextrin glucanotransferase to act on a solution, comprising either liquefied starch or dextrin and L-ascorbic acid as materials, and then allowing a glucoamylase to act on resulting solution to obtain a solution, containing 2-O-α-D-glucosyl-L-ascorbic acid, with 2-O-α-D-glucosyl-L-ascorbic acid production yield of at least 27 wt%; purification of obtained solution, containing 2-O-α-D-glucosyl-L-ascorbic acid, to obtain content of 2-O-α-D-glucosyl-L-ascorbic acid of more than 86 wt%, in terms of dry weight of solid substance; precipitation of anhydrous crystalline 2-O-α-D-glucosyl-L-ascorbic acid from purified solution with content of 2-O-α-D-glucosyl-L-ascorbic acid of more than 86 wt%, in terms of dry weight of solid substance, by method of controlled cooling or by pseudo-controlled cooling; collection of precipitated anhydrous crystalline 2-O-α-D-glucosyl-L-ascorbic acid and ageing, drying and optionally milling collected anhydrous crystalline 2-O-α-D-glucosyl-L-ascorbic acid without dissolution and recrystallisation to produce a composition in form of particles, containing anhydrous crystalline 2-O-α-D-glucosyl-L-ascorbic acid, which contains 2-O-α-D-glucosyl-L-ascorbic acid in an amount in terms of dry weight of solid substance, of more than 98.0 wt%, but less than 99.9 wt% has crystallinity of anhydrous crystalline 2-O-α-D-glucosyl-L-ascorbic acid at least 90%, when calculating based on x-ray powder diffraction profile of composition in form of particles; where method of controlled cooling is a method of cooling, where temperature T of solution at a time t is expressed by formula T=T0-(T0-Tf)(t/τ)3, where τ is operating time, set for crystallisation stage, T0 is temperature of solution at beginning of crystallisation, and Tf is target temperature after crystallisation; and where pseudocontrolled cooling method is a method of cooling, where liquid temperature T is given linearly or gradually decreases relative to time t, so that (t0-Tm) is at least 5 %, but less than 50 % of total temperature change (T0-Tf), where Tm is liquid temperature at moment of time t=τ/2.

EFFECT: method enables to obtain a product which is considerably harder to cake.

7 cl, 10 tbl, 8 ex, 6 dwg

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