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    公开号:SU724086A3
    申请号:SU772535803
    申请日:1977-10-27
    公开日:1980-03-25
    发明作者:Игараси Кикуо
    申请人:Сионоги Энд Ко Лтд (Фирма)；
    IPC主号:
    专利说明:

    specified values; the dotted line indicates the presence or absence of a double bond in which all functional groups except the 1-amino group are protected with protecting groups with N-oxysuccinimide carboxylic acid ester of the general formula </ BR> where R and n have the indicated meanings, in the presence of a solvent: dimethyl forms and its mixtures with water or water, preferably in the presence of dimethylformamide, at 0-25 ° C, preferably at 20-25 ° C, followed by removal of the protective groups and isolation of the desired product as a free base or salt.  Example 1  Preparation of N-oKCHcyKUHHamido-M-benzyloxycarbonyl-4-hydroxypipervdin-4-carboxyl1.  BUT.  To a solution of 10.0 g (53 mmol) of M-benzylpiperidium in 14 Mat of dry tetrahydrofuran was added 23 ml (3.6 eq.  25% by weight of a solution of hydrogen cyanide in tetrahydrofuran at room temperature and hold the resulting mixture for 1 hour.  The scavenger and the remaining reagents are removed by evaporation under reduced pressure, thus obtaining 11.50 g of N-benzylpiperidone cyanohydride as a colorless crystalline substance with m. square  79-85C.   B.  A mixture of 9.477 g (43.9 mmol) of crude N-benzylpiperidone cyanine prepared as described above and 18.4 ml (5 eq. ) concentrated hydrochloric acid is heated on a water bath for 1 h.  During the course of the reaction, ammonium chloride precipitated as crystals.  The reaction mixture is cooled, the ammonium chloride formed as a precipitate is collected by filtration and washed with cooled acetone.  The combined filtrates and the resulting solution are distilled to dryness under reduced pressure, resulting in 12.65 gels; The residue was dissolved in 65 ml of water mixed with 28 ml of water containing 3.97 g of sodium acetate, and the mixture was distilled off under reduced pressure.  The precipitate obtained is triturated with 150 ml of acetone and the insoluble material is extracted with a mixture of chloroform and methanol (9: 1).  The insoluble sodium chloride is filtered off and the filtrate is evaporated under reduced pressure.  The semi-precipitated precipitate is dissolved in 6 ml of water mixed with acetone, and the mixture is kept overnight in a refrigerator.  The precipitated crystals are collected by filtration and rinsed with cooled acetone, then 8.70 g of M-benzyl-4-hydroxy-piidin-4-carboxylic acid (84.5%), t. square 260.5262 ° C (decomposition).  The crystals contain 1 mole of water of crystallization, which is lost on drying at a temperature of 75 ° C under reduced pressure for 5 hours.  Weight is reduced to 7.92 g (77% yield).  AT.  A solution of 2.35 g (10 mmol) obtained as described above, 1M-benzyl-4-hydroxypiperidine-4-carboxylic acid, dissolved in a mixture of 20 ml of water, 20 ml of methanol and 2.0 ml of concentrated hydrochloric acid, is subjected to catalytic hydrogenation in a hydrogen atmosphere for 23 hours in the presence of 1 g of 10% palladium / charcoal.  After completion of the reaction, the catalyst is removed by filtration and washed with an aqueous solution of methanol.  Together, the filtrate and the solution obtained after washing were evaporated under reduced pressure, to give 1.95 g of precipitate as light yellow crystals.  They are dissolved in 15 ml of water containing 1.25 g (30 mmol) of sodium hydroxide and 2.05 g (12 mmol) of benzyloxycarbonyl chloride and added to the resulting solution for 30 minutes at room temperature while moving.  The mixture was kept at room temperature for 2 hours, after which 0.5 ml of a 10% aqueous solution of sodium hydroxide was added to it.  The mixture is washed with ether and the pH of the aqueous layer is adjusted to 2 with 10% hydrochloric acid in order to obtain an oily material, which is extracted with ether.  The esterified solution is washed with water and dried over anhydrous sodium sulphate, yielding 2.53 g (yield 9%) of M-benzsh10xycarbonyl-4-hydroxypiperidine-4-carboxylic acid as a pale yellow oily substance.  G.  To a suspension of 2.49 g (8.92 mmol) of N-benzyloxycarbonyl-4-hydroxypiperidine-4-carboxylic acid and 1.02 g (8.92 mmol) of N-OKCH succinimide in 40 ml of dry ethyl acetate is added a solution of 1.84 g (8.92 mmol) of dicyclohexylcarbodiimide in 5 ml of dry ethyl acetate, the mixture is stirred at room temperature overnight, then cooled in an ice bath.  The insoluble material is removed by filtration, washed with chilled ethyl acetate.  The combined filtrate and solution obtained by washing are evaporated under reduced pressure to obtain 3.34 g of N-hydroxysuccinimido-M-beisyloxycarbonyl-4-hydroxypiperidine.  This compound is used for subsequent acylation without further purification.  PRI me R 2.  Preparation of N-oxysuccinimido-D L-1 -benzyloxycarbonyl-3-hydroxypyrrolidine-3-carboxylate.  A, To a solution of 16.40 g (9.45 mmol) of 1-benzyl-3-pyrrolidone in 5 ml of tetrahydrofuran was added 40 ml (343 mmol) of a 25% solution of HCN in tetrahydrofuran, and the mixture was incubated for 5 hours .  The solvent and the excess reagent are evaporated under reduced pressure.  The precipitate is dissolved in 38.5 ml of concentrated hydrochloric acid and the solution is heated on a water bath for 1 hour.  After cooling, the precipitated ammonium chloride is filtered off and washed with 4 ml of cooled hydrochloric acid and then with acetone.  The combined filtrate and the solution obtained during the washing are evaporated under reduced pressure.  The precipitate is dissolved in 50 ml of an aqueous solution of 8 g of sodium acetate, and the mixture (the pH value of which is 5) is evaporated under reduced pressure.  The precipitate was dissolved in chloroform, and the insoluble sodium chloride was removed by filtration and washed with chloroform.  The chloroform layer extracts 50 ml of an aqueous solution containing 4 g of sodium hydroxide (the mixture then has a pH of 9).  The aqueous layer is washed once with chloroform, slowly absorbed into 200 ml of Amberlite TR-120B (H) at a rate of 3-4 seconds per drop).  Kojjomiy washed with 400 ml of water and eluted with 700 ml of 1N.  ammonium hydroxide.  The eluate is evaporated under reduced pressure and the resulting precipitate is recrystallized from 80 ml of water, yielding 12.048 g of a colorless needle with m. ttl  184-189 ° C (decomposition).  Needle crystals contain water of crystallization, which is removed at 70 ° C and under reduced pressure for two days, as a result of 10.45 g of 01-benz1-3-hydroxypyrrolidine-3-carboxylic acid (yield 50% Found : C 64.10; H 6.94; N 6.25.  CijHisNOj- 1/5 HjO Calculated,%: C 6t, 17; H 6.90; N 6.23.  B.  To a solution of 885 g (4.0 mmol) of DL-1-benzyl-3-hydroxypyrrolidine-3-carboxylic acid, dissolved in a 50% aqueous solution of dioxane, 1 ml of concentrated hydrochloric acid is added and the mixture is catalytically hydrogenated in the presence of 400 mg of 10% palladium / charcoal.  The catalyst was removed by filtration and washed with an aqueous solution of dioxane.  The combined filtrate and the solution obtained after industrialization was evaporated under reduced pressure to obtain a precipitate, which was recrystallized from acetone, thus obtaining 610 mg of DL-3-hydroxypyrrolidine-3-carboxylic acid hydrochloride as colorless prisms (yield 91%), T. Ш1.  201-210 ° C (decomposition).  AT.  To a solution of 610 mg (3.6 mmol) of DL-3-hydroxypyrrolidine-3-carboxylic acid hydrochloride dissolved in 10 ml of water, is added 6 ml of an aqueous solution of 456 mg (3 eq.) Of sodium hydroxide and 750 mg (1.2 ml) eq) benzyloxycarbonyl chloride at room temperature and when moved, with CMeci; stir for 2 hours.  The pH of the reaction mixture was adjusted to 11 with 10% aqueous sodium hydroxide solution, washed twice with ether, then adjusted to pH 2 with 10% hydrochloric acid, and extracted three times with ether.  The extract obtained is dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain 800 mg of a precipitate, which is crystallized from a mixture of ether and petroleum ether.  The crystals obtained (t. square  117- 133 ° C) is recrystallized from a mixture of ether and methylene chloride, thus obtaining 595 mg of OA-benzyloxycarbonyl-3-hydroxypyrrolidine-3-carboxylic acid (yield 61.6%), t. square  142-144 ° C.  Found,%: C 58.86; H 5.76; N 5.16.  CiaHisNOs Calcined,%: C 58.86; H 5.70; N 5.28.  G.  To a solution of 266 mg (2.00 mmol) of DL-1-benyloxycarbonyl-3-hydroxypyrrolidine-3-carboxylic acid in 30 ml of ethyl acetate, with heating, 115 mg (1.0 mmol) of powdered 1-oxysuccincymide are added.  Immediately after the addition, colorless crystals (206 mg, 1.0 mmol) of dicyclohexycarbodiimide precipitate.  The mixture is moved for 1.5 hours and left overnight in the refrigerator.  The crystals collect the njTCM filtration and the insoluble material is washed with ethyl acetate.  Combined together, the filtrate solution, obtained after washing, is evaporated under reduced pressure, and half-hemisphere is 90 mg of precipitate (t. square  154--16lC).  It is recrystallized from a mixture of acetone and hexane, while 277 mg of M-oxysuccinimidoDL-1-benzyloxycarbonyl-3-hydroxypyrrolidine-3-carboxylate is obtained in a yield of 76.6%, t. square  159 - 161 C.  PRI me R 3.  Preparation of l-N- (4-OKCHiridin-4-carbonyl) kanamycin A.   Krastviru 1.55 g (2.5 mmol) of 6-N-rpeT-btoxycarbonylcanamycin A in 24 ml of 50%, 2-dimethoxyethane is added dropwise paciBOp 1.53 g (4.06 mmol) of N-oxysuccinimido-M-benzyloxycarbonyl- 4-hydroxypiperidine-4-carboxylate in 24 ml, 1,2-benzylbxycarbonyl-4-hydroxypiperidine-4-carboxylate in 24 ml of 1,2-dimethoxyethane at a temperature of 2-3 ° C for 2 hours.  The mixture was stirred at room temperature for 14.5 hours. The mixture was evaporated under reduced pressure at a temperature of / tanks below 35 ° C, thus obtaining 3.2. g precipitate as a white foamy substance.  This precipitate was dissolved in 20 ml, iO% -Hoft trifluoroacetic acid, and the mixture was kept at room temperature for 1 and 2/3 h and evaporated under reduced pressure.  The precipitate is dissolved in 50 ml of a 50% aqueous solution of methanol and catalytically hydrogenated in the presence of 1 g of 1 p% Ngr. o catalyst palladium / charcoal of atmospheric 6d6 kind for 3 h.  After completion of the reaction, the palladium activated angle is removed by filtration and the solvent is evaporated under reduced pressure.  The precipitate (4.15 g) was dissolved in 10 ml of water, absorbed in 100 ml of Amberlite CG-50, the column was washed with 240 ml of water and eluted with 100 ml of water and 1000 ml I n.  ammonium hydroxide according to the gradient method (one fraction 10 g).  Eluate (474 mg) from fractions. 91-108 are dissolved in 10 ml of water, absorbed with 10 ml of Amberlite CG-50 (NH), the column is washed with 20 ml of water, and 1000 ml of water and 1000 ml of 1N are basified.  ammonium hydroxide.  Eluates (27 mg) from fractions 89-95 are dissolved in 6 ml of Water, 100 ml of Amberlite CG-50 (NH) are absorbed on the column, the column is washed with 30 ml of water and eluted with 1000 ml of water and 1000 ml of 1N.  hydroxide oxide. ammonium.  The eluate (270 mg) from fractions 89-95 is dissolved in 6 ml of water, absorbed on a column of 100. ml of Amberlite CG - 50 (NHj) and the column is washed with 30 ml of water and eluted with 1000 ml of water and 0.5N.  hydrate ok xy ammonium.  Eluates from fractions 159-166 are lyophilized to obtain 71 kg of the desired substance (6% yield), 1 86.3 ± 1.2 (with 1.016, water).  Thin layer chromatography (Kieselgel 60 p254Merk): Rf 0.45 (dilution system: l - methanol: concentrated ammonia 1: 1, to compare Rf A to kanamycin 0.25.  PRI me R 4.  Getting 1-N- (4-hydroxypiperidine-4-carbonyl) tobramycin.    A, K solution of 9.0 g (17.9 mmol) of it dihydrate p6aMniuina c. 122 ml of water were added 322 ml of pyrillin, 32 ml of triethipamine and 2.64 g (18.4 mmol) of tert-butyloxycarbonylazide, and the mixture was allowed to stand at room temperature overnight, after which it was evaporated under reduced pressure at 40 ° s  The resulting product is dissolved in 100 ml of water and the resulting mixture is evaporated under reduced pressure.  This operation is repeated three times to obtain 11.95 g of sediment.  The precipitate is dissolved in 60 ml of water and absorbed with 450 ml of Amberlite CG-50 (NHt).  The column is washed with 1500 ml of water, and a ml of water and 1000 ml of 0.1 N are eluted.  ammonium hydroxide by the method of gradients and then 4100 mg 0.1 n.  ammonium hydroxide (one fraction 15 g).  From fraction 141-200, 4.70 g of 6-N-tert-butylrxycarbonyltrabracinin is obtained (yield 46.4%), +110.3 ± 1.6 ° (from 0.940, water).  Found C, 47.79; H 7.92; N 11.78.  C23H4sNOl / 2H2O: Calculated,%: G 47.90; H 8.00; N 12.15.  B.  To a solution of 1.81 g (3.0 mol) of 6-N-TpeT-6yTHnoxycarbonyltrabramycin obtained by the above method, dissolved in a mixture of 5 ml of water and 5 ml of dimethylformamide, 8 ml of a solution of dimethylformamide containing 0.748 g (3.0 mmol) of N are added dropwise -benzyloxycarbonylsuccinimide, at a temperature.  stirring for 2 hours, after which the mixture is moved at the same temperature overnight.  The solvent was distilled off under reduced pressure, yielding 3.17 g of precipitate.  It is dissolved in 40 ml of water and extracted four times using 30 ml of ethyl acetate each time.  The aqueous layer was adsorbed with 100 ml of Amberlite CG - 50 (NH) and eluted with 1700 ml of water and 1700 ml of 0.05 n.  ammonium hydroxide solution according to the tradition method and then. 1500 ml of 0.1 N ammonium hydroxide solution (18 ml one fraction).  Fractions.  13-132 provide 877 mg of 6-N-tert-by-Ih0-xyroxybonyl-2-N-benzyloxycarbonyltobramycin (40% yield).  Fractions 114-132 are lyophilized and the physical characteristics of the obtained ve + 87.2 ± 1.2 (c 1.023, water) are determined.  Found,%: C 51.09; H 7.47; N 9.37.  C3, Hs, NsO, 3-15 HjO Calculated,%: C 51.09; H 7.47; N 9.61.  Thin layer chromatography (Kieselgel 60 P254Merk): Rf 0.19 (solvent system - isopropyl alcohol: concentrated aqueous ammonia: chloroform in a ratio of 4: 1: 1), for comparison Rf 6-N-N-tert-butyloxycarboin-to-tri-amycin 0.08.  AT.  To a solution of 387 mg (0.566 mmol) of 6-M-tert-butyloxycarbonyl-2-Y-benz; toxncarbonyl-tobramycin dissolved in an aqueous solution of dimethylformamide, a solution of 319 mg (0.679 mmol) of N-oxysuccinimine benzyloxycarbonyl-ox-oxypeptimetricpe-hippioxypeppexy-benzoxycarbonyl-oxieppi-benzoxycarbonyl-oxieppi-benzoxycarbonyl-oximericane benzyloxycarbonyl-hydroxymethyl benzyloxycarbonyl-hydroxymethyl benzyloxycarbonyl-hydroxymethyl benzyloxycarbonyl-hydroxymethylhydroxymethyl benzyl oxy-hippiophenol is added; -carboxylate in 6 ml of dimethylformamide at a temperature of 0-3 ° C with stirring for 1 and 1/3 h.  The mixture was stirred at the same temperature for 50 minutes and then at room temperature for 4 hours and evaporated under reduced pressure to obtain 787 mg of precipitate as a colorless foamy substance.  It is dissolved in 8 ml of 90% trifluoroacetic acid, the resulting mixture is stirred at room temperature for 1.5 hours and evaporated to a precipitate, which is subjected to catalytic hydrogenation using 334 mg of 5% palladium / charcoal in mixtures of 3 ml of acetic acid.  0.6 ml and 3 ml of methanol.  After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated under reduced pressure to obtain 1.25 g of precipitate.  It is dissolved in 4 ml of water and 30 ml of Amberlite CG-50 (NHj) are adsorbed on the flask.  The column is washed with 300 ml of water and the substance is eluted with 1000 ml of water and 1000 ml of 1N.  ammonium hydroxide solution by the gradient method (one fraction 10 ml).  .  Eluates (47 mg) of fractions 68-73 were dissolved in 1.5 ml of water, absorbed into 5 ml of Amberlite CG-50 (NH) and eluted with 480 ml of water and 480 ml of 1N.  ammonium hydroxide solution according to the method of fadiente (one fraction 5 ml).  Eluates of fractions 40-43 were lyophilized to obtain 16 mg of the title compound (4.9% yield).  Thin layer chromatography (Kieselgel 60 p254 Merck): Rf 0.35 (solvent system: ethanol: 1: 1 concentrated aqueous ammonia solution, for comparison Rf tobramycin 0.58.  PRI me R 5.  Preparation of DL-l-N- (3-hydroxypyrrolidin-3-carboshshtrabramycin.  BUT.  A mixture of 174 mg (0.3 mmol) of tetra-N-formyltobramidine and 131 mg (1.2 eq. ) N-hydroxysuccinimido-D N-benzyloxycarbonyl-3-hydroxypyrroline din-3-carboxylate, dissolved in 10 ml of dimethylformamide, is held at room temperature for 2 hours and then evaporated under reduced pressure to give a precipitate, which is thoroughly converted into a powder with ethyl acetate.  The precipitate which then falls is collected by filtration and washed with ethyl acetate.  The precipitate (266 mg) is hydrogenated with 140 mg of G0% palladium / charcoal mixture in 10 ml of water, 8 ml of methanol and a drop of acetic acid.  After removal of the katapizaguer, 204 mg of crude tetra-N-formyl-DL-N- (3-hydroxypyrrolidine-3-carbonyl tobramidine are obtained.  B.  Hydrolysis of tetra-M-formyl-OY- (3-hydroxypyrrolidine-3-carbonyl) tobramycin with 5% hydrochloric acid and methanol (1).  To a solution containing 204 mg of tetra-N-formyl-DL-lN- (3-hydroxypyrrolidine-3-carbonyl) tobramycin, obtained during this operation, in 0.22 ml of water, add 1.96 ml, 5% - hydrochloric acid / methanol solution (mixture of 0.55 ml of concentrated hydrochloric acid and 6 ml of methanol) and the mixture is hydrogenated in an oil bath for 22.5 hours.  After the completion of the reaction, the hydrochloric acid was removed by treating the mixture with 6 ml of Amberlite HS-45, the resin was removed by filtration and washed with water.  United. together, the filtrate and the solution obtained after washing are evaporated under reduced pressure, to thereby give 197 mg of residue.  The residue is chromatographed on a column with 25 ml of Amberlite CG-50 (NH,), eluted with 500 ml of 1N.  ammonium hydroxide solution according to the gradient method.  The eluates from fractions 64-78 are condensed and lyophilized to obtain 98 mg of DL-1-N- (3-hydroxypyrrolidine-3-carbonyl) tobramycin, the yield in the form of bicarbonate 46.4% 85.2 + 1.2 ° (with 1,046, water).  Thin layer chromatography (Kiegelgel 60 p2 5 4 Merck): Rf 0.40 (solution system istels - isopropyl alcohol: 1: 1 concentrated aqueous ammonia solution, to compare Rf tobramycin 0.56.  Hydrolysis with a mixture of hydrazine acetic acid hydrate (2).  A solution (pH 6) of 206 mg of the tetra-N-form-1-DL-lN (3-hydroxypyrrolidine-3-carbonyl) tobramycin solution prepared according to the indicated method, dissolved in a mixture of 20 ml of hydrazine monohydrate and 2.63 ml of acetic acid, is heated under reflux with stirring for 6 hours  The reaction mixture is diluted with water to 400 ml, absorbed with 100 ml of Amberlite CG-50 (NH), rinsed with 1 l of water and 1 l of 0.4% ammonium hydroxide solution, and then eluted with a 0.8% hydroxide solution. mmoni (one fraction 12 ml).  Fractions 20--47 are evaporated under reduced pressure and lyophilized to obtain, at 25 mg of the title compound (yield in IH 3 CO 3 salt 54 ,.  S + 77.0 + 1.1 (c 1.064, water).  Found, C 40.62; H 6.39; N 10.80.  С2зН44МбО ,, - ЗНлСО, Calculated, Г 40.7. five; H 6.57; N 10. 96  11 This compound is identical to the compound, field 7 by method 1.  PRI me R 6.  Preparation of (1-ethyl-3-hydroxypyrrolidine-3-carbonyltobramycin.  A mixture of 1-benzyloxycarboxy-1-3-hydroxypyrrolidine-3-carboxylic acid (2.090 g; 7.16 mol 3,2,6 3 -tetra-M-forms1 1 gram (4.160 g; 7.16 mmol), N-oxysucdinimide (910 mg) and dicyclohexylcarbodiimide (1.870 g; 7.16 mmol) is dissolved in 50 ml of M, N-dimethyl formamide and kept at room temperature overnight.  Precipitated 1-didolatexylurea is filtered off and washed with 5 ml of S, M-dimethylformamide.  To the combined (silt and wash solution, 550 mg of ethyladetate is added in order to form a precipitate.  The precipitate is collected by filtration.  It is washed with ethyladetate, dissolved in water and evaporated under reduced pressure.  The residue (6.00 g) is dissolved in a mixture of IB with 70 ml of water and 20 ml of methanol and subjected to a mixture of catalytic hydroxide, in the presence of 2.00 g of 10% palladium charcoal under reduced pressure.  After the amount of hydrogen gas is absorbed in advance, the catalyst is filtered and washed with water.  The combined filtrate and solution after washing was evaporated under reduced pressure, to thereby give 5.30 g of 1-N- (3-hydroxypyrrolidine-3-carbonyl) 3, 2b, 3-tetraformyltrabramidine as a colorless powder.  To a solution of 228 mg (0.63 mmol) of the powder, dissolved in 0.5 ml of water, is added 1.0 ml of acetonitrile.  The mixture is divided into two layers and then made homogeneous by the addition of 0.48 ml of an aqueous solution of acetal degal, semi-oo immediately after the distillate (solution of 6.77 g of acetaldehyde in 50 ml of water).  Immediately thereafter, sodium cyanoborohydride is added when the pH of the solution is changed to 7 with acetic acid.  After | After 2 hours, the mixture is concentrated and 4 ml of ethyl acetate, J2, is added to the residue, after which the mixture is thoroughly mixed. | The resulting powder is filtered off and collected, washed with ethyl acetate, dissolved with a mixture of 1 ml of isopropyl alcohol water, slowly absorbed on a column with 13.5 g of kieselgel (manufactured by Merck) and eluted with a mixture of isopropyl alcohol, concentrated ammonium hydroxide and chloroform (2: 1: 1), one fraction 10 g, The eluates from fractions 11-30 are evaporated and the residue is dissolved in 14.6 ml of water, to which 1.46 ml of hydrazine hydrate and 1.73 ml of acetic acid are added.  The mixture is heated under reflux for 6 hours, diluted with 261 ml of water and absorbed amberlite CG-50 (NHj) at 73 MP.  The column is washed with 680 ml of water and then eluted with a 0.4% aqueous solution of ammonium hydroxide (one South fraction).  The eluates of fractions 70-75 are treated with decolorizing charcoal, the mixture is filtered through a Pyrex glass filter and the filtrate is evaporated to obtain 52.2 mg of the title compound as a colorless powder.  It is dissolved in a small amount of water, the pH of the solution is adjusted to a value of 4.6 with 0.095 n.  sulfuric acid solution and evaporated under reduced pressure.  Ethanol is added and the precipitate is then collected by filtration, washed with ethanol, dissolved in water, treated with desaturated charcoal (Norit A), filtered through a pyrex filter to obtain a sample for microanalysis, and pyophilized to obtain 103 mg of the corresponding sulfate (total yield 41.9%), -I- 72.5i ± 1.1 ° (with 1.031, in water).  Found: C, 28.61; H 6.93; N 7.93; S 8.48.  C25H48N6022 2H2S04 10.5 Hj O Calculated: C, 28.97; H 7.15; N 8.06; S 7.69.  The table shows the compounds obtained in a similar way.
    ABOUT
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    权利要求:
    Claims (3)
    [1]
    - 2 The formula of the invention 1. The method of obtaining the derivatives of amine 171 dicoside of the general formula (c
    KB u
    R is hydrogen, lower alkyl or benzyl;
     R corresponds to aminomethyl, hydroxymethyl methylamine or 1-methylaminoethyl; Rj, Pz and Nb correspond independently of each other to a hydrogen atom or hydroxy; R4 corresponds to hydroxy or amino; RS corresponds to amino or methylamino; RT corresponds to hydroxy or methyl; Rg corresponds to a hydrogen atom, hydroxymethyl or carbamoyloxymethyl;
    the dotted line corresponds to the presence or absence of a double bond;
    n corresponds to an integer, when the value is 1 or 2,
    or salts thereof, characterized in that the aminoglycoside of the general formula KI
    I T M
      XX / "H2. MoOAL",
    UuOR T.
    u
    noos
    (CIS) p
    where R and p have the indicated meanings,
    in the presence of a solvent: dimethylformamide or its mixture with water or water, at a temperature of 0-25 ° C, followed by removal of the protective groups and isolation of the desired product as a free base or salt.
    [2]
    2. The method according to claim 1, that is, that dimethylformamide is used as a solvent.
    [3]
    3. The method according to claim 1, wherein the reaction is carried out at 20-25 ° C.
    Sources of information taken in the room during examination 1. Schröder E., Lubke K. Peptides, p. 1. M., Mir, 1967, p. 116. 18 where RI, R, Rj, R4, RS-Re. R-; And Rg has the indicated meanings, the dotted line corresponds to the presence or absence of a double bond in which all functional groups are present. In addition to the -amino groups, protected by protecting groups, they are reacted and interacting with the carboxylic acid N-oxysuccinimide ester of the general formula
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    US4418193A|1983-11-29|Method of producing 2-epi-fortimicin A
    CA1046057A|1979-01-09|1-N-| XK-62-2 AND METHOD OF PRODUCTION THEREOF
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    PT67134B|1979-03-16|
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    PH14183A|1981-03-26|
    AU2986577A|1979-04-26|
    AR221833A1|1981-03-31|
    RO73517A|1980-11-30|
    IE45788B1|1982-12-01|
    PT67134A|1977-11-01|
    IE45788L|1978-04-28|
    GR61696B|1978-12-11|
    IL53208A|1981-05-20|
    GB1583366A|1981-01-28|
    AU512230B2|1980-10-02|
    IL53208D0|1977-12-30|
    FR2369295B1|1980-01-18|
    ES463684A1|1978-07-01|
    PL105730B1|1979-10-31|
    FI773229A|1978-04-29|
    HU177261B|1981-08-28|
    PL201732A1|1978-07-17|
    CA1085830A|1980-09-16|
    ZA775314B|1978-07-26|
    BE860048A|1978-04-24|
    US4166114A|1979-08-28|
    DK478677A|1978-04-29|
    MX4324E|1982-03-24|
    NZ185168A|1980-10-24|
    SE7711992L|1978-04-29|
    FR2369295A1|1978-05-26|
    AT348125B|1979-01-25|
    NL7711843A|1978-05-03|
    DE2748257A1|1978-05-03|
    JPS5356661A|1978-05-23|
    ATA771277A|1978-06-15|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP13011976A|JPS5356661A|1976-10-28|1976-10-28|Novel amino glycoside antibiotics derivatives|
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