CN105524129A - Etimicin sulfate preparation method - Google Patents
Etimicin sulfate preparation method Download PDFInfo
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- C07H15/234—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2
- C07H15/236—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings attached to non-adjacent ring carbon atoms of the cyclohexane rings, e.g. kanamycins, tobramycin, nebramycin, gentamicin A2 a saccharide radical being substituted by an alkylamino radical in position 3 and by two substituents different from hydrogen in position 4, e.g. gentamicin complex, sisomicin, verdamycin
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Abstract
The invention provides an etimicin sulfate preparation method. The method comprises the following steps: taking gentamycin C1a base, dissolving the gentamycin C1a base in a certain proportion of a solvent, adding a certain proportion of a complexing agent to complex, adding a certain proportion of an amino group protection agent, keeping for a certain time, adding a certain proportion of a precipitating agent, stirring above materials, filtering the obtained mixture, adding a certain proportion of an acetylation reagent to the above obtained filtrate, reacting for a certain time, adding a certain proportion of a reducing agent, reacting for a certain time, removing an amino protection group, adding a certain proportion of water, carring out vacuum concentration under certain conditions to remove the solvent, adjusting the pH value with ammonia water, adsorbing with macro-porous resin, carrying out gradient separating purification with diluted ethanol, collecting an etimicin solution with a certain purity, carrying out vacuum concentration under certain conditions, adding sulfuric acid to adjust the pH value, adding a certain proportion of active carbon, decolorizing, filtering, and drying to obtain etimicin sulfate according with relevant standards.
Description
Technical field:
The present invention relates to medicinal chemistry art, a kind of preparation method of glucoside-containing component, specifically a kind of preparation method of Etimicin sulfate.
Background technology:
Etimicin sulfate (Etimicinsulfate) is that China scientific research personnel develops voluntarily, having the semi-synthetic aminoglycoside antibiotics of efficient, low toxicity, antimicrobial agent a new generation of independent intellectual property right, is the anti-infectives uniquely obtaining first class national new drug certificate.
The various infection that Etimicin sulfate injection liquid is applicable to intestinal bacteria to its sensitivity, Klebsiella pneumoniae, Serratia genus, citrobacter, enterobacter, acinetobacter, proteus, bloodthirsty hemophilus influenza, Pseudomonas aeruginosa and staphylococcus etc. cause.Clinical studies show this product has good curative effect to following infection.Respiratory tract infection: as acute bronchitis, acute episode of chronic bronchitis, community's pulmonary infection etc.; Kidney and urogenital infections: as acute pyelonephritis, urocystitis, chronic pyelonephritis or chronic cystitis acute attack etc.; Skin soft tissue and other infect: as skin and soft tissue infection, wound, wound and the infection in operation postpartum and other sensitive organisms infect.
At present, the technique that suitability for industrialized production Etimicin sulfate uses is the technique (application number: 93112412.3) of patent report.Its key step is: add Cobaltous diacetate after Gentamicin C1a alkali dissolves in a solvent, diacetyl oxide, generate 3, 2 ', 6 ',-three-N-ethanoyl Gentamicin C1as (P1), concentrated through extracting, concentrated solution passes into hydrogen sulfide removing cobalt ion, drying obtains the P1 that purity is 90%-95%, then acetaldehyde is added, reductive agent hydrogenation is used in 0-5 DEG C of ice-water bath, obtain 3, 2 ', 6 ',-three-N-ethanoyl-1-N ethyl Gentamicin C1a (P2), the higher P2 of purity is obtained after adsorptive type macroporous resin is separated, the P2 that purity is higher adds the sodium hydroxide solution of 1N, hydrolysis backflow 48 hours, hydrolyzed solution is separated through adsorptive type macroporous resin and obtains 1-N-EthagentamycinC1a (Etimicin) solution that purity is more than 90%, acid adding salify, activated carbon decolorizing, lyophilize, obtain Etimicin salt.It is tediously long to there is such as synthetic route in this technique, and yield is low; Twice macroporous resin purification, produces a large amount of waste liquid; Add without protective group step when acetaldehyde reacts, the problems such as side reaction is many.
Summary of the invention:
The object of the present invention is to provide a kind of preparation method of Etimicin sulfate, it is short that the method has synthetic route, produces waste water few, the advantage that the good side reaction of reaction specificity is few.
Preparation method of the present invention, comprises the following steps:
Step 1) get Gentamicin C1a alkali, solvent is added according to Gentamicin C1a alkali weight 5-10 ratio doubly, wherein said solvent is the one in methyl alcohol, ethanol, DMSO, methylene dichloride, trichloromethane, DMF, THF, acetonitrile, and stirring and dissolving obtains solution
Step 2) solution adds complexing agent by the amount 1-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said complexing agent is the one in Cobaltous diacetate, neutralized verdigris, zinc acetate, rose vitriol, copper sulfate, zinc sulfate, stirs to obtain reaction solution 1,
Step 3) reaction solution 1 adds amino protecting agent by the amount 2-6 equivalent doubly of Gentamicin C1a alkaloid substance; wherein said amino protecting agent is the one in trityl chloride, dimethoxy benzaldehyde, aubepine, phenyl aldehyde; stirring reaction 1-5 hour, obtains reaction solution 2
Step 4) reaction solution 2 adds precipitation agent by the amount 2-6 equivalent doubly of Gentamicin C1a alkaloid substance, and filter after stirring, wherein said precipitation agent is the one in ammonium oxalate, potassium oxalate, sodium oxalate, ammonium phosphate, sodium phosphate, potassiumphosphate, obtains reaction solution 3,
Step 5) reaction solution 3 adds acetylation reagent by the amount 1-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said acetylation reagent is the one in Acetyl Chloride 98Min., Glacial acetic acid, diacetyl oxide, and stirring reaction 1-5 hour obtains reaction solution 4,
Step 6) reaction solution 4 adds reductive agent by the amount 5-10 equivalent doubly of Gentamicin C1a alkaloid substance, wherein said reductive agent is the one in sodium cyanoborohydride, red aluminium, sodium borohydride, triacetyl oxygen sodium borohydride, POTASSIUM BOROHYDRIDE, borine, Lithium Aluminium Hydride, stirring reaction 2-8 hour, obtain reaction solution 5
Step 7) reaction solution 5 adds its volume 3-6 water doubly vacuum tightness below 80 DEG C and do not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, macroporous resin adsorption is used after regulating PH to 12-14 with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition
Step 8) concentrated solution adds sulphur acid for adjusting pH to 4.0 ~ 7.0, and the activated carbon decolorizing adding its weight 5% ~ 20% filters, after freeze-drying, vacuum drying or spraying dry and get final product.
Adopt above-mentioned technique to prepare Etimicin sulfate, simple to operate, be easy to industrialization, a supporting transfer tank of popular response still and filtration unit, can complete whole building-up reactions, the technique that the patent that application number is 93112412.3 is reported is then much complicated.Secondly, technique provided by the present invention only need carry out a macroporous resin chromatography purification can obtain Etimicin sulfate, compare the technique that patent that application number is 93112412.3 is reported, decrease the process of a macroporous resin chromatography purification, produce waste liquid amount and significantly reduce; And the synthetic in technique provided by the present invention can focus on by most of Distillation recovery, meet the theory of environmental protection, the technique that the patent that application number is 93112412.3 is reported is then processed as DMSO etc. is incorporated in waste water by synthesis organic solvent.3rd, composition principle of the present invention first adopts transition metal complex to protect the 1-N of parent nucleus Gentamicin C1a amino, add the amino that amino protecting agent protects other positions, redeposition is removed the complexing of transition metal and is discharged 1-N amino, then acetylation reagent is added, make 1-N acetylated, react finally by reduction of amide, direct is ethyl by the Reduction of amide groups of 1-N position, simultaneously slough again the amido protecting group at other positions, thus directly obtain target product, and the technique that the patent that application number is 93112412.3 is reported adds acetaldehyde in the process of the 1-N position of parent nucleus Gentamicin C1a access ethyl, acetaldehyde can be exposed with parent nucleus the side reaction of hydroxyl generation aldol condensation, therefore technique side reaction provided by the present invention to produce impurity less less, specificity is better.
Preparation method of the present invention is through screening and obtains, and as the solvent used, amino protecting agent, precipitation agent, acetylation reagent, reductive agent, the selection of the methods such as gradient elution separation purifying, preferred preparation method of the present invention in an embodiment.
Embodiment:
Further illustrate the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Get Gentamicin C1a alkali, add the methyl alcohol of Gentamicin C1a alkali weight 6 times, stirring and dissolving obtains solution, add the Cobaltous diacetate of 2 times of equivalents of the amount of Gentamicin C1a alkaloid substance, stir to obtain reaction solution 1, add the aubepine of amount 4 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 2 hours, obtain reaction solution 2, add the ammonium oxalate of the amount 2 times of Gentamicin C1a alkaloid substance, filter after stirring, obtain reaction solution 3, add the Acetyl Chloride 98Min. of amount 2 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 2 hours, obtain reaction solution 4, add the POTASSIUM BOROHYDRIDE of 7 times of equivalents of the amount of Gentamicin C1a alkaloid substance, stirring reaction 6 hours, obtain reaction solution 5, the water vacuum tightness below 80 DEG C adding 5 times of volumes does not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, the rear macroporous resin adsorption of pH to 13 is regulated with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition, add sulfuric acid and regulate PH to 4.5, the activated carbon decolorizing adding above-mentioned concentrated solution weight 18% filters, freeze-drying and get final product.
Embodiment 2
Get Gentamicin C1a alkali, add the methylene dichloride of Gentamicin C1a alkali weight 7 times, stirring and dissolving obtains solution, add the zinc acetate of amount 3 times of equivalents of Gentamicin C1a alkaloid substance, stir to obtain reaction solution 1, add the trityl chloride of amount 6 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 3 hours, obtain reaction solution 2, add the amount 2-4 ammonium phosphate doubly of Gentamicin C1a alkaloid substance, filter after stirring, obtain reaction solution 3, add the Glacial acetic acid of amount 3 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 3 hours, obtain reaction solution 4, add the triacetyl oxygen sodium borohydride of 10 times of equivalents of the amount of Gentamicin C1a alkaloid substance, stirring reaction 4 hours, obtain reaction solution 5, the water vacuum tightness below 80 DEG C adding 5 times of volumes does not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, the rear macroporous resin adsorption of pH to 13.5 is regulated with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition, add sulfuric acid and regulate PH to 6.0, the activated carbon decolorizing adding its weight 15% filters, spraying dry and get final product.
Embodiment 3
Get Gentamicin C1a alkali, add the DMSO of Gentamicin C1a alkali weight 10 times, stirring and dissolving obtains solution, add the amount 2-3 zinc sulfate doubly of Gentamicin C1a alkaloid substance, stir to obtain reaction solution 1, add the dimethoxy benzaldehyde of the amount 3 times of Gentamicin C1a alkaloid substance, stirring reaction 1 hour, obtain reaction solution 2, add the amount 2-4 potassiumphosphate doubly of Gentamicin C1a alkaloid substance, filter after stirring, obtain reaction solution 3, add the diacetyl oxide of the amount 1.5 times of Gentamicin C1a alkaloid substance, stirring reaction 1 hour, obtain reaction solution 4, add the sodium cyanoborohydride of the amount 5 times of Gentamicin C1a alkaloid substance, stirring reaction 4 hours, obtain reaction solution 5, the water vacuum tightness below 80 DEG C adding 3 times of volumes does not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, the rear macroporous resin adsorption of PH to 13 is regulated with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition, the activated carbon decolorizing adding its weight 10% filters, vacuum drying and get final product.
Illustrate: above embodiment only in order to the present invention is described and and unrestricted technical scheme described in the invention; Therefore, although this specification sheets with reference to each above-mentioned embodiment to present invention has been detailed description, those of ordinary skill in the art should be appreciated that and still can modify to the present invention or equivalent to replace; And all do not depart from technical scheme and the improvement thereof of the spirit and scope of the present invention, it all should be encompassed in right of the present invention.
Claims (8)
1. a preparation method for Etimicin sulfate, is characterized in that, comprises the following steps:
Step 1, get Gentamicin C1a alkali, add a certain proportion of solvent, stirring and dissolving obtains solution,
Step 2, solution add a certain proportion of complexing agent, stir to obtain reaction solution 1,
Step 3, reaction solution 1 add a certain proportion of amino protecting agent, and stirring reaction certain hour obtains reaction solution 2,
Step 4, reaction solution 2 add a certain proportion of precipitation agent, filter, obtain reaction solution 3 after stirring,
Step 5, reaction solution 3 add a certain proportion of acetylation reagent, and stirring reaction certain hour obtains reaction solution 4,
Step 6, reaction solution 4 add a certain proportion of reductive agent, and stirring reaction certain hour obtains reaction solution 5,
Step 7, reaction solution 5 add a certain proportion of water vacuum concentration removal under certain condition solvent, use macroporous resin adsorption, Diluted Alcohol gradient separations purifying after regulating PH with ammoniacal liquor, collect the Etimicin solution of certain purity, vacuum concentration obtains concentrated solution under certain condition
Step 8, concentrated solution add sulfuric acid and are adjusted to certain pH, add a certain proportion of activated carbon decolorizing and filter, after drying and get final product.
Wherein,
Solvent described in step 1 is the one in methyl alcohol, ethanol, DMSO, methylene dichloride, trichloromethane, DMF, THF, acetonitrile, and described solvent additional proportion is 5-10 times of Gentamicin C1a alkali weight,
Complexing agent described in step 2 is the one in Cobaltous diacetate, neutralized verdigris, zinc acetate, rose vitriol, copper sulfate, zinc sulfate, and described complexing agent additional proportion is 1-4 times of equivalent of the amount of Gentamicin C1a alkaloid substance,
Amino protecting agent described in step 3 is the one in trityl chloride, dimethoxy benzaldehyde, aubepine, phenyl aldehyde; amino protecting agent additional proportion is 2-6 times of equivalent of the amount of Gentamicin C1a alkaloid substance; the described stirring reaction time is 1-5 hour
Precipitation agent described in step 4 is the one in ammonium oxalate, potassium oxalate, sodium oxalate, ammonium phosphate, sodium phosphate, potassiumphosphate, and described precipitation agent additional proportion is 2-6 times of equivalent of the amount of Gentamicin C1a alkaloid substance,
Acetylation reagent described in step 5 is the one in Acetyl Chloride 98Min., Glacial acetic acid, diacetyl oxide, and described acetylation reagent additional proportion is 1-4 times of equivalent of the amount of Gentamicin C1a alkaloid substance, and the described stirring reaction time is 1-5 hour,
Reductive agent described in step 6 is the one in sodium cyanoborohydride, red aluminium, sodium borohydride, triacetyl oxygen sodium borohydride, POTASSIUM BOROHYDRIDE, borine, Lithium Aluminium Hydride, described reductive agent additional proportion is 5-10 times of equivalent of the amount of Gentamicin C1a alkaloid substance, the described stirring reaction time is 2-8 hour
The ratio of the water described in step 7 is 3-6 times of reaction solution 5 volume, vacuum concentration condition be temperature less than 80 DEG C vacuum tightnesss not higher than 0.2 normal atmosphere, described ammoniacal liquor regulates PH to be 12-14, and described Diluted Alcohol gradient is 5%-40%, described purity is > 95%
PH scope described in step 8 is 4.0 ~ 7.0, and gac additional proportion is 5% ~ 20% of concentrated solution weight, and described drying mode is the one in freeze-drying, vacuum drying, spraying dry.
2. preparation method according to claim 1, is characterized in that, comprises the following steps:
Step 1) get Gentamicin C1a alkali, solvent is added according to Gentamicin C1a alkali weight 5-10 ratio doubly, wherein said solvent is the one in methyl alcohol, ethanol, DMSO, methylene dichloride, trichloromethane, DMF, THF, acetonitrile, and stirring and dissolving obtains solution
Step 2) solution adds complexing agent by the amount 1-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said complexing agent is the one in Cobaltous diacetate, neutralized verdigris, zinc acetate, rose vitriol, copper sulfate, zinc sulfate, stirs to obtain reaction solution 1,
Step 3) reaction solution 1 adds amino protecting agent by the amount 2-6 equivalent doubly of Gentamicin C1a alkaloid substance; wherein said amino protecting agent is the one in trityl chloride, dimethoxy benzaldehyde, aubepine, phenyl aldehyde; stirring reaction 1-5 hour, obtains reaction solution 2
Step 4) reaction solution 2 adds precipitation agent by the amount 2-6 equivalent doubly of Gentamicin C1a alkaloid substance, and filter after stirring, wherein said precipitation agent is the one in ammonium oxalate, potassium oxalate, sodium oxalate, ammonium phosphate, sodium phosphate, potassiumphosphate, obtains reaction solution 3,
Step 5) reaction solution 3 adds acetylation reagent by the amount 1-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said acetylation reagent is the one in Acetyl Chloride 98Min., Glacial acetic acid, diacetyl oxide, and stirring reaction 1-5 hour obtains reaction solution 4,
Step 6) reaction solution 4 adds reductive agent by the amount 5-10 equivalent doubly of Gentamicin C1a alkaloid substance, wherein said reductive agent is the one in sodium cyanoborohydride, red aluminium, sodium borohydride, triacetyl oxygen sodium borohydride, POTASSIUM BOROHYDRIDE, borine, Lithium Aluminium Hydride, stirring reaction 2-8 hour, obtain reaction solution 5
Step 7) reaction solution 5 adds its volume 3-6 water doubly vacuum tightness below 80 DEG C and do not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, macroporous resin adsorption is used after regulating PH to 12-14 with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition
Step 8) concentrated solution adds sulphur acid for adjusting pH to 4.0 ~ 7.0, and the activated carbon decolorizing adding its weight 5% ~ 20% filters, after freeze-drying, vacuum drying or spraying dry and get final product.
3. preparation method according to claim 1, is characterized in that, comprises the following steps:
Step 1) get Gentamicin C1a alkali, add solvent according to Gentamicin C1a alkali weight 5-8 ratio doubly, wherein said solvent is the one in methyl alcohol, methylene dichloride, DMSO, trichloromethane, THF, and stirring and dissolving obtains solution,
Step 2) solution adds complexing agent by the amount 2-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said complexing agent is the one in neutralized verdigris, zinc acetate, copper sulfate, rose vitriol, stirs to obtain reaction solution 1,
Step 3) reaction solution 1 adds amino protecting agent by the amount 3-6 equivalent doubly of Gentamicin C1a alkaloid substance; wherein said amino protecting agent is the one in trityl chloride, dimethoxy benzaldehyde, aubepine; stirring reaction 1-4 hour, obtains reaction solution 2
Step 4) reaction solution 2 adds precipitation agent by the amount 2-5 equivalent doubly of Gentamicin C1a alkaloid substance, and filter after stirring, wherein said precipitation agent is the one in potassium oxalate, sodium oxalate, ammonium phosphate, potassiumphosphate, obtains reaction solution 3,
Step 5) reaction solution 3 adds acetylation reagent by the amount 1-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said acetylation reagent is the one in Acetyl Chloride 98Min., diacetyl oxide, and stirring reaction 1-4 hour obtains reaction solution 4,
Step 6) reaction solution 4 adds reductive agent by the amount 6-10 equivalent doubly of Gentamicin C1a alkaloid substance, wherein said reductive agent is the one in sodium cyanoborohydride, sodium borohydride, triacetyl oxygen sodium borohydride, POTASSIUM BOROHYDRIDE, borine, stirring reaction 3-7 hour, obtains reaction solution 5
Step 7) reaction solution 5 adds its volume 3-5 water doubly vacuum tightness below 80 DEG C and do not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, macroporous resin adsorption is used after regulating pH to 13-14 with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition
Step 8) concentrated solution adds sulphur acid for adjusting pH to 4.0 ~ 6.0, and the activated carbon decolorizing adding its weight 10% ~ 20% filters, after freeze-drying or spraying dry and get final product.
4. preparation method according to claim 1, is characterized in that, comprises the following steps:
Step 1) get Gentamicin C1a alkali, add solvent according to Gentamicin C1a alkali weight 5-7 ratio doubly, wherein said solvent is the one in methyl alcohol, methylene dichloride, DMSO, THF, and stirring and dissolving obtains solution,
Step 2) solution adds complexing agent by the amount 2-3 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said complexing agent is the one in neutralized verdigris, zinc acetate, rose vitriol, stirs to obtain reaction solution 1,
Step 3) reaction solution 1 adds amino protecting agent by the amount 3-5 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said amino protecting agent is the one in trityl chloride, aubepine, and stirring reaction 1-3 hour obtains reaction solution 2,
Step 4) reaction solution 2 adds precipitation agent by the amount 2-4 equivalent doubly of Gentamicin C1a alkaloid substance, and filter after stirring, wherein said precipitation agent is the one in potassium oxalate, sodium oxalate, potassiumphosphate, obtains reaction solution 3,
Step 5) reaction solution 3 adds acetylation reagent by the amount 1-3 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said acetylation reagent is the one in Acetyl Chloride 98Min., diacetyl oxide, and stirring reaction 1-3 hour obtains reaction solution 4,
Step 6) reaction solution 4 adds reductive agent by the amount 6-9 equivalent doubly of Gentamicin C1a alkaloid substance, wherein said reductive agent is the one in sodium cyanoborohydride, sodium borohydride, triacetyl oxygen sodium borohydride, POTASSIUM BOROHYDRIDE, stirring reaction 3-7 hour, obtains reaction solution 5
Step 7) reaction solution 5 adds its volume 3-4 water doubly vacuum tightness below 80 DEG C and do not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, macroporous resin adsorption is used after regulating pH to 13-14 with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition
Step 8) concentrated solution adds sulphur acid for adjusting pH to 4.0 ~ 5.5, and the activated carbon decolorizing adding its weight 10% ~ 15% filters, after freeze-drying or spraying dry and get final product.
5. preparation method according to claim 1, is characterized in that, comprises the following steps:
Step 1) get Gentamicin C1a alkali, add solvent according to Gentamicin C1a alkali weight 5-6 ratio doubly, wherein said solvent is the one in methyl alcohol, methylene dichloride, THF, and stirring and dissolving obtains solution,
Step 2) solution adds complexing agent by the amount 2-3 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said complexing agent is the one in zinc acetate, rose vitriol, stirs to obtain reaction solution 1,
Step 3) reaction solution 1 adds amino protecting agent by the amount 3-4 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said amino protecting agent is the one in trityl chloride, aubepine, and stirring reaction 2-3 hour obtains reaction solution 2,
Step 4) reaction solution 2 adds precipitation agent by the amount 2-3 equivalent doubly of Gentamicin C1a alkaloid substance, and filter after stirring, wherein said precipitation agent is the one in sodium oxalate, potassiumphosphate, obtains reaction solution 3,
Step 5) reaction solution 3 adds acetylation reagent by the amount 2-3 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said acetylation reagent is the one in Acetyl Chloride 98Min., diacetyl oxide, and stirring reaction 2-3 hour obtains reaction solution 4,
Step 6) reaction solution 4 adds reductive agent by the amount 8-9 equivalent doubly of Gentamicin C1a alkaloid substance, and wherein said reductive agent is the one in sodium cyanoborohydride, sodium borohydride, triacetyl oxygen sodium borohydride, and stirring reaction 5-7 hour, obtains reaction solution 5,
Step 7) reaction solution 5 adds its volume 3-4 water doubly vacuum tightness below 80 DEG C and do not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, macroporous resin adsorption is used after regulating pH to 13-14 with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition
Step 8) concentrated solution adds sulphur acid for adjusting pH to 4.5 ~ 5.5, and the activated carbon decolorizing adding its weight 12% ~ 15% filters, after freeze-drying or spraying dry and get final product.
6. preparation method according to claim 1, is characterized in that, comprises the following steps:
Get Gentamicin C1a alkali, add the methyl alcohol of Gentamicin C1a alkali weight 6 times, stirring and dissolving obtains solution, add the Cobaltous diacetate of 2 times of equivalents of the amount of Gentamicin C1a alkaloid substance, stir to obtain reaction solution 1, add the aubepine of amount 4 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 2 hours, obtain reaction solution 2, add the ammonium oxalate of the amount 2 times of Gentamicin C1a alkaloid substance, filter after stirring, obtain reaction solution 3, add the Acetyl Chloride 98Min. of amount 2 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 2 hours, obtain reaction solution 4, add the POTASSIUM BOROHYDRIDE of 7 times of equivalents of the amount of Gentamicin C1a alkaloid substance, stirring reaction 6 hours, obtain reaction solution 5, the water vacuum tightness below 80 DEG C adding 5 times of volumes does not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, the rear macroporous resin adsorption of pH to 13 is regulated with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition, add sulfuric acid and regulate PH to 4.5, the activated carbon decolorizing adding above-mentioned concentrated solution weight 18% filters, freeze-drying and get final product.
7. preparation method according to claim 1, is characterized in that, comprises the following steps:
Get Gentamicin C1a alkali, add the methylene dichloride of Gentamicin C1a alkali weight 7 times, stirring and dissolving obtains solution, add the zinc acetate of amount 3 times of equivalents of Gentamicin C1a alkaloid substance, stir to obtain reaction solution 1, add the trityl chloride of amount 6 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 3 hours, obtain reaction solution 2, add the amount 2-4 ammonium phosphate doubly of Gentamicin C1a alkaloid substance, filter after stirring, obtain reaction solution 3, add the Glacial acetic acid of amount 3 times of equivalents of Gentamicin C1a alkaloid substance, stirring reaction 3 hours, obtain reaction solution 4, add the triacetyl oxygen sodium borohydride of 10 times of equivalents of the amount of Gentamicin C1a alkaloid substance, stirring reaction 4 hours, obtain reaction solution 5, the water vacuum tightness below 80 DEG C adding 5 times of volumes does not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, the rear macroporous resin adsorption of pH to 13.5 is regulated with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition, add sulfuric acid and regulate PH to 6.0, the activated carbon decolorizing adding its weight 15% filters, spraying dry and get final product.
8. preparation method according to claim 1, is characterized in that, comprises the following steps:
Get Gentamicin C1a alkali, add the DMSO of Gentamicin C1a alkali weight 10 times, stirring and dissolving obtains solution, add the amount 2-3 zinc sulfate doubly of Gentamicin C1a alkaloid substance, stir to obtain reaction solution 1, add the dimethoxy benzaldehyde of the amount 3 times of Gentamicin C1a alkaloid substance, stirring reaction 1 hour, obtain reaction solution 2, add the amount 2-4 potassiumphosphate doubly of Gentamicin C1a alkaloid substance, filter after stirring, obtain reaction solution 3, add the diacetyl oxide of the amount 1.5 times of Gentamicin C1a alkaloid substance, stirring reaction 1 hour, obtain reaction solution 4, add the sodium cyanoborohydride of the amount 5 times of Gentamicin C1a alkaloid substance, stirring reaction 4 hours, obtain reaction solution 5, the water vacuum tightness below 80 DEG C adding 3 times of volumes does not remove solvent higher than vacuum concentration under 0.2 atmospheric condition, the rear macroporous resin adsorption of PH to 13 is regulated with ammoniacal liquor, the Diluted Alcohol gradient separations purifying of 5%-40%, collect the Etimicin solution of purity > 95%, below 80 DEG C, vacuum tightness does not obtain concentrated solution higher than vacuum concentration under 0.2 atmospheric condition, the activated carbon decolorizing adding its weight 10% filters, vacuum drying and get final product.
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| CN111039999A (en) * | 2019-12-25 | 2020-04-21 | 无锡济民可信山禾药业股份有限公司 | Synthesis method of etimicin impurity |
| CN111825732A (en) * | 2020-07-18 | 2020-10-27 | 无锡济煜山禾药业股份有限公司 | Method for preparing etimicin sulfate by ultrasonic wave |
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