CN103833804B - A kind of synthetic method of Etimicin sulfate - Google Patents
A kind of synthetic method of Etimicin sulfate Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of Etimicin sulfate, Gentamicin C1a and zinc acetate and aceticanhydride is the steps include: to be obtained by reacting 3, 2 ', 6 '-three (N-acetyl) Gentamicin C1a, by 3, 2 ', 3 are obtained by reacting with iodoethane after 6 '-three (N-acetyl) Gentamicin C1a separation and purification, 2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a, 3, 2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a obtains the Etimicin aqueous solution after sodium hydroxide hydrolysis, the Etimicin aqueous solution is through HZD-2 macroporous resin adsorption, separation and purification, concentrated, become vitriol, charcoal takes off, drying obtains Etimicin sulfate finished product.Present invention process yield is 55%, and yield is high, and meets the requirement of " Chinese Pharmacopoeia " (2010 editions).
Description
Technical field
The present invention relates to the preparation method of Etimicin sulfate, particularly relate to the preparation method being synthesized Etimicin sulfate by Gentamicin C1a, belong to the semi-synthetic technical field of aminoglycoside drug.
Background technology
Etimicin sulfate is a kind of semi-synthetic water soluble amino sugar tobramycin antibiotic newly, and its mechanism of action suppresses the normal protein synthesis of sensitive organism.Etimicin sulfate is Broad spectrum antibiotics, to most of gram-positive microorganism and negative bacterium, there is good anti-microbial effect, especially good anti-microbial activity is all had to intestinal bacteria, the white pneumobacillus of Cray, Serratia, Salmonellas and staphylococcus etc., all there is anti-microbial activity to the S. aureus L-forms of part gentamicin, micronomicin and Kefzol resistance, intestinal bacteria, the white pneumobacillus of Cray, also have certain anti-microbial activity to the generation part staphylococcus of penicillinase and the staphylococcus of part low-level methicillin resistance.The features such as Etimicin sulfate has efficiently, low toxicity, antimicrobial agent, has a broad antifungal spectrum, has good anti-microbial effect to multiple pathogenic bacteria, all has good curative effect to respiratory tract infection, kidney and urinary system infection, skin structure infections.
The existing synthetic method of Etimicin sulfate is: Gentamicin C1a and Cobaltous diacetate and aceticanhydride are obtained by reacting 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a (being called for short P1), 3 are obtained by reacting with acetaldehyde and sodium borohydride by after P1 separation and purification, 2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a (being called for short P2), P2 obtains the Etimicin aqueous solution after sodium hydroxide hydrolysis, the Etimicin aqueous solution through macroporous resin adsorption, separation and purification, concentrated, become that vitriol, charcoal are de-, drying obtains Etimicin sulfate finished product.This existing Etimicin sulfate synthetic method craft yield is 36%, and yield is low.
Summary of the invention
Technical problem to be solved by this invention is: the preparation method providing the Etimicin sulfate that a kind of process recovery ratio is high.
Technical solution of the present invention is: a kind of Etimicin synthetic method, comprises the following steps:
(1) Gentamicin C1a is added methyl alcohol and stir 30 minutes, fully mix, obtain Gentamicin C1a methanol solution, add methyl alcohol 20 milliliters calculating by every 1 gram of Gentamicin C1a;
(2) solution that step (1) obtains is added zinc acetate, be warming up to 45 DEG C, react and obtain reaction solution in 3 hours, add zinc acetate 4 grams calculating by every 3 grams of Gentamicin C1as;
(3) reaction solution that step (2) obtains is added triethylamine, then add aceticanhydride, be warming up to 55 DEG C, react 4 hours, then this reaction solution is concentrated, evaporate to dryness, obtains yellow solid, add triethylamine 20 milliliters by every 3 grams of Gentamicin C1as, every 3 grams of Gentamicin C1as add aceticanhydride 2 milliliters calculating;
(4) yellow solid that step (3) obtains is added purified water, open stirring, make abundant dissolving, add 10 milliliters of purified water by every 1 gram of yellow solid and calculate;
(5) aqueous solution that step (4) obtains is added sodium sulphite, be warming up to 45 DEG C, react 1 hour, solution produces and precipitates and form yellow turbid solution, adds 2 grams of sodium sulphite calculate by every 1 gram of Gentamicin C1a;
(6) solution step (5) obtained filters, and yellow solid discards after adding purified water washing, obtains pale yellow filtrate, adds 1 milliliter of purified water calculate by every 1 gram of yellow solid;
(7) pale yellow filtrate step (6) obtained is concentrated, evaporate to dryness obtains 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a;
(8) step (7) obtained 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a adds dimethyl formamide and dissolves, and by every 1 gram 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a adds 5 milliliters of dimethyl formamides and calculates;
(9) solution that step (8) obtains is added sodium bicarbonate, drip iodoethane, be warming up to 60 DEG C, react 4 hours, make complete reaction, add 1 gram of sodium bicarbonate by every 10 grams of Gentamicin C1as, every 10 grams of Gentamicin C1as add 1.2 milliliters of iodoethane and calculate;
(10) solution that step (9) obtains is concentrated evaporate to dryness and obtain 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a;
(11) step (10) obtained 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a adds purified water, open stirring, make abundant dissolving, by every 1 gram 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a adds 20 milliliters of purified water and calculates;
(12) solution that step (11) obtains being added concentration is 30% sodium hydroxide solution, is adjusted to pH11, is warming up to 100 DEG C, is hydrolyzed 6 hours, maintains pH11, make to react completely, obtain the Etimicin aqueous solution between the reaction period with the sodium hydroxide solution that concentration is 30%;
(13) the Etimicin aqueous solution that step (12) obtains being added concentration is that 10% sulfuric acid is adjusted to pH6.5;
(14) solution that step (13) obtains is added HZD-2 macroporous resin, adsorb 4 hours;
(15) resin step (14) obtained and solution, be separated with 80 order stainless steel meshs, liquid discards, and washs after resin being filled post, resolves, and concentrates and obtains concentrated solution;
(16) concentrated solution that step (15) obtains is added the sulfuric acid that concentration is 98%, be adjusted to pH5.5, make into vitriol, obtain Etimicin sulfate concentrated solution;
(17) the Etimicin sulfate concentrated solution that step (16) obtains is added gac, filter, spraying dry obtains Etimicin sulfate finished product, adds gac 100 grams calculating by every 1 liter of Etimicin sulfate concentrated solution.
Technique effect of the present invention is: Gentamicin C1a and zinc acetate and aceticanhydride are obtained by reacting 3 by the present invention, 2 ', 6 '-three (N-acetyl) Gentamicin C1a (being called for short P1), 3 are obtained by reacting with iodoethane by after P1 separation and purification, 2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a (being called for short P2), P2 obtains the Etimicin aqueous solution after sodium hydroxide hydrolysis, the Etimicin aqueous solution through HZD-2 macroporous resin adsorption, separation and purification, concentrated, become that vitriol, charcoal are de-, drying obtains Etimicin sulfate finished product.Present invention process yield is 55%, and yield is high, the requirement that quality meets " Chinese Pharmacopoeia " (2010 editions).
The concrete difference of the present invention and existing technique:
A () the present invention zinc acetate and Gentamicin C1a are obtained by reacting P1, existing technique is obtained by reacting P1 with Cobaltous diacetate and Gentamicin C1a; This step can improve P1 yield 7.9%, because make reaction more complete with zinc acetate.
B () the present invention iodoethane and P1 are obtained by reacting P2, existing technique is obtained by reacting P2 with acetaldehyde and sodium borohydride, and this step can improve P2 yield 17.1%, because make reaction more complete with iodoethane.
C () the present invention HZD-2 macroporous resin adsorbs Etimicin, washing, and separation and purification once altogether, existing technique is adsorbed respectively P2 and Etimicin with adsorptive type macroporous resin, separation and purification secondary altogether, this step can improve Etimicin yield 2%, because decrease step.
As shown in Table 1 and Table 2, table 1 is Etimicin sulfate three batches of product data of existing explained hereafter to concrete data, and table 2 produces three batches of product data of Etimicin sulfate for the present invention.
Process recovery ratio=(Etimicin sulfate weight/Gentamicin C1a weight) × 100%
Table 1
Table 2
Process recovery ratio=(Etimicin sulfate weight/Gentamicin C1a weight) × 100%
The requirement of Etimicin sulfate " Chinese Pharmacopoeia " (2010 editions): this product is white or off-white powder, very easily dissolve in water, almost insoluble in methyl alcohol, acetone and Glacial acetic acid, specific optical rotation: ﹢ 100 °-﹢ 115 °, pH value should be 4.0-6.5, and vitriol should be 31.5-35%, moisture≤10%, residue on ignition≤0.5%, single impurity≤2.5%, total impurities≤5.0%.
Embodiment
The present invention is the preparation method being synthesized Etimicin by Gentamicin C1a, specifically comprises the following steps:
1,1500 grams of Gentamicin C1as are got, add volume be 50 liters sandwich heating and agitating function stainless steel reaction tank in, then in this retort, add 30 liters of methyl alcohol (adding methyl alcohol 20 milliliters calculating by 1 gram of Gentamicin C1a), stir 30 minutes, mixing speed 80 turns of ∕ minute, Gentamicin C1a is fully mixed in methyl alcohol, obtains Gentamicin C1a methanol solution.
Gentamicin C1a is one of gentamicin component, is white or off-white powder, soluble in water, is slightly soluble in methyl alcohol, acetone and other organic solvent, the chemical structural formula of Gentamicin C1a:
The molecular weight of Gentamicin C1a: 449
The molecular formula of Gentamicin C1a: C
19h
39n
5o
7
2, the methanol solution that step 1 obtains is added zinc acetate 2000 grams and (add zinc acetate 4 grams calculating by 3 grams of Gentamicin C1as
),be warming up to 45 DEG C with the stainless steel reaction tank of sandwich heating and stirring, react 3 hours, whether making to react completely obtains reaction solution, react completely with Liquid Detection reaction solution.
Step 2 Liquid Detection step is:
(2-1) extract reaction solution 1 milliliter, add 24 milliliters of purified water, mix, with filter paper filtering, obtain diluting soln,
(2-2) get the diluting soln of 1 milliliter of step (2-1), add 99 milliliters of purified water, mix, obtain secondary dilution solution,
(2-3) the secondary dilution solution of 20 microlitre steps (2-2) is got, injection liquid chromatography, record collection of illustrative plates,
(2-4) when collection of illustrative plates display Gentamicin C1a content is less than 0.5%, can think that reaction terminates.
3, the reaction solution that step 2 obtains is added triethylamine 10 liters, add aceticanhydride 1 liter again and (add triethylamine 20 milliliters by 3 grams of Gentamicin C1as, 3 grams of Gentamicin C1as add aceticanhydride 2 milliliters calculating), be warming up to 55 DEG C, react 4 hours, sandwich heating and stir stainless steel reaction tank in make raw material complete reaction, whether react completely by Liquid Detection, reaction solution is concentrated, evaporate to dryness, obtain yellow solid, yellow solid main component is: 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a (P1), zinc acetate and a small amount of methyl alcohol and triethylamine.
4, (add 10 milliliters of purified water by 1 gram of yellow solid to add, open stirring with the stainless steel reaction tank of sandwich heating and stirring, mixing speed 80 turns of ∕ minute, make abundant dissolving the yellow solid that step 3 obtains to be added purified water 35 liters.
5, the aqueous solution that step 4 obtains is added 3000 grams, sodium sulphite (adding 2 grams of sodium sulphite by 1 gram of Gentamicin C1a to add), be warming up to 45 DEG C, react 1 hour, solution produces and precipitates and form yellow turbid solution, the composition of yellow turbid solution is: P1, zinc sulphide and water, and mixed throw out is in a liquid zinc sulphide.
6, solution solid-liquid filter step 5 obtained is filtered, add 1200 order filter clothes, yellow solid discards after adding 2 liters of purified water (adding 1 milliliter of purified water by 1 gram of yellow solid to calculate) washing, obtain pale yellow filtrate, the composition of yellow solution is 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a (P1) and water.Pale yellow filtrate comprises the liquid sum of filtering the liquid that obtains and washing yellow solid and obtaining.
7, pale yellow filtrate step 6 obtained is concentrated, evaporate to dryness, obtains solid P1; Concentrated, evaporate to dryness is by interlayer heating and opens stirring, mixing speed 80 turns of ∕ minute, the stainless steel reaction tank heating with sandwich and stir simultaneously.Reaction product removes zinc sulphide after filtration, removes water through concentrated evaporate to dryness, residue P1
The title of P1: 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a
The chemical structural formula of P1:
Molecular weight: 575
Molecular formula: C
25h
45n
5o
10
8, solid P1 step 7 obtained adds dimethyl formamide (being called for short DMF) 10 liters (adding 5 milliliters of DMF by 1 gram of solid P1), and open stirring, mixing speed 80 turns of ∕ minute, make abundant dissolving;
9, the solution that step 8 obtains is added sodium bicarbonate 150 grams, drip iodoethane 180 milliliters, be warming up to 60 DEG C, react 4 hours, make complete reaction, whether react completely by Liquid Detection.
The present embodiment liquid phase detection method is:
(9-1) extract reaction solution 1 milliliter, add 24 milliliters of purified water, mix, with filter paper filtering,
(9-2) get the diluting soln of 1 milliliter of step (9-1), add 99 milliliters of purified water, mix,
(9-3) diluting soln of 20 microlitre steps (9-2) is got, injection liquid chromatography, record collection of illustrative plates,
(9-4), when collection of illustrative plates display P1 content is less than 0.5%, reaction can be terminated.
The present embodiment adds 1 gram of sodium bicarbonate by 10 grams of Gentamicin C1as, and 10 grams of Gentamicin C1as add 1.2 milliliters of iodoethane and calculate.
10, the solution that step 9 obtains is concentrated evaporate to dryness and obtain solid P2; With the stainless steel reaction tank that sandwich heats and stirs; heated by interlayer and open stirring simultaneously, mixing speed 80 turns of ∕ minute, amino not protected on iodoethane and P1 is obtained by reacting product P 2; after removing dimethyl formamide and unnecessary iodoethane by concentrated evaporate to dryness, residue P2.
The title of P2: 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a
The chemical structural formula of P2:
The molecular weight of P2: 603
The molecular formula of P2: C
27h
49n
5o
10
11, solid P2 step 10 obtained adds purified water 35 liters, opens stirring, and mixing speed 80 turns of ∕ minute, make abundant dissolving, and add 20 milliliters of purified water by 1 gram of solid P2 and calculate, mixing speed 80 turns of ∕ minute, the time is 30 minutes.
12, the solution that step 11 obtains is added the sodium hydroxide solution that concentration is 30%, be adjusted to pH11,100 DEG C are warming up to the stainless steel reaction tank of sandwich heating and stirring, be hydrolyzed 6 hours, maintain PH11(and soda acid pH value with the sodium hydroxide solution that concentration is 30% between the reaction period and reach 11), make to react completely, whether react completely by Liquid Detection, obtain the Etimicin aqueous solution.
The chemical structural formula of Etimicin:
Molecular weight: 477
Molecular formula: C
21h
39n
5o
7
13, Etimicin aqueous solution step 12 obtained add concentration be 10% sulfuric acid be adjusted to pH6.5.
14, the solution that step 13 obtains is added HZD-2 macroporous resin 12 liters, mixing speed 30 turns of ∕ minute, adsorb 4 hours, make absorption complete, inhale remaining liquid by Liquid Detection, judge whether that absorption completely;
Its main physical and chemical index of the present embodiment HZD-2 macroporous resin:
Step 14 Liquid Detection is:
(14-1) the remaining liquid 10 milliliters of suction is got, with filter paper filtering,
(14-2) filtrate 20 microlitre of step 1 is got, injection liquid chromatography, record collection of illustrative plates,
(14-3), when collection of illustrative plates display Etimicin content is for trace (being less than 50ug/ml), namely absorption completely.
15, resin step 14 obtained and solution, be separated with 80 order stainless steel meshs, liquid discards, be the ammoniacal liquor 240 liters washing of 0.15% by concentration after resin being filled post, with the ammoniacal liquor 36 liters parsing that concentration is 4.5%, desorbed solution thin film concentrator is concentrated, is concentrated into 5 liters.
Resin dress post of the present invention, washing, parsing, concentrated concrete grammar:
(15-1) post is filled: resin being loaded blade diameter length ratio is that in the line with rubber post of 1:20, loading amount reaches 90%,
(15-2) wash: be that 0.15% ammoniacal liquor passes in resin column by concentration, flow velocity is 1/3rd of amount of resin, and flux is 20 times of amount of resin,
(15-3) resolve: pass in resin column with the ammoniacal liquor that concentration is 4.5%, flow velocity is 1/10th of amount of resin, and flux is 3 times of amount of resin,
(15-4) concentrated: to concentrate with thin film concentrator, be concentrated into 1/20th of desorbed solution volume.
16, the concentrated solution that step 15 obtains is added the sulfuric acid that concentration is 98%, be adjusted to pH5.5, become vitriol, obtain Etimicin sulfate finished fluid.
17, Etimicin sulfate finished fluid step 16 obtained adds gac 500 grams (adding gac 100 grams calculating by 1 liter of Etimicin sulfate concentrated solution), be warming up to 55 DEG C, stir 4 hours, filter by solid-liquid filter, add 1200 order filter clothes, carry out spraying dry with spray tower, obtain Etimicin sulfate finished product 830 grams.
With spray tower spraying dry concrete grammar be: spray in tower by Etimicin sulfate finished fluid by shower nozzle, the hot blast in spray tower is dry by vaporific Etimicin sulfate finished fluid, forms pulverous finished powder.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment to invention has been detailed description, for a person skilled in the art, it still can be modified to the technical scheme described in foregoing embodiments, or carries out equivalent replacement to wherein portion of techniques feature.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection of the present invention.
Claims (1)
1. a synthetic method for Etimicin sulfate, is characterized in that, comprises the following steps:
(1) Gentamicin C1a is added methyl alcohol and stir 30 minutes, fully mix, obtain Gentamicin C1a methanol solution, add methyl alcohol 20 milliliters calculating by every 1 gram of Gentamicin C1a;
(2) solution that step (1) obtains is added zinc acetate, be warming up to 45 DEG C, react and obtain reaction solution in 3 hours, add zinc acetate 4 grams calculating by every 3 grams of Gentamicin C1as;
(3) reaction solution that step (2) obtains is added triethylamine, then add aceticanhydride, be warming up to 55 DEG C, react 4 hours, then this reaction solution is concentrated, evaporate to dryness, obtains yellow solid, add triethylamine 20 milliliters by every 3 grams of Gentamicin C1as, every 3 grams of Gentamicin C1as add aceticanhydride 2 milliliters calculating;
(4) yellow solid that step (3) obtains is added purified water, open stirring, make abundant dissolving, add 10 milliliters of purified water by every 1 gram of yellow solid and calculate;
(5) aqueous solution that step (4) obtains is added sodium sulphite, be warming up to 45 DEG C, react 1 hour, solution produces and precipitates and form yellow turbid solution, adds 2 grams of sodium sulphite calculate by every 1 gram of Gentamicin C1a;
(6) solution step (5) obtained filters, and yellow solid discards after adding purified water washing, obtains pale yellow filtrate, adds 1 milliliter of purified water calculate by every 1 gram of yellow solid;
(7) pale yellow filtrate step (6) obtained is concentrated, evaporate to dryness obtains 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a;
(8) step (7) obtained 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a adds dimethyl formamide and dissolves, and by every 1 gram 3,2 ', 6 '-three (N-acetyl) Gentamicin C1a adds 5 milliliters of dimethyl formamides and calculates;
(9) solution that step (8) obtains is added sodium bicarbonate, drip iodoethane, be warming up to 60 DEG C, react 4 hours, make complete reaction, add 1 gram of sodium bicarbonate by every 10 grams of Gentamicin C1as, every 10 grams of Gentamicin C1as add 1.2 milliliters of iodoethane and calculate;
(10) solution that step (9) obtains is concentrated evaporate to dryness and obtain 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a;
(11) step (10) obtained 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a adds purified water, open stirring, make abundant dissolving, by every 1 gram 3,2 ', 6 '-three (N-acetyl)-1-ethyl Gentamicin C1a adds 20 milliliters of purified water and calculates;
(12) solution that step (11) obtains being added concentration is 30% sodium hydroxide solution, is adjusted to pH11, is warming up to 100 DEG C, is hydrolyzed 6 hours, maintains pH11, make to react completely, obtain the Etimicin aqueous solution between the reaction period with the sodium hydroxide solution that concentration is 30%;
(13) the Etimicin aqueous solution that step (12) obtains being added concentration is that 10% sulfuric acid is adjusted to pH6.5;
(14) solution that step (13) obtains is added HZD-2 macroporous resin, adsorb 4 hours;
(15) resin step (14) obtained and solution, be separated with 80 order stainless steel meshs, liquid discards, and washs after resin being filled post, resolves, and concentrates and obtains concentrated solution;
(16) concentrated solution that step (15) obtains is added the sulfuric acid that concentration is 98%, be adjusted to pH5.5, make into vitriol, obtain Etimicin sulfate concentrated solution;
(17) the Etimicin sulfate concentrated solution that step (16) obtains is added gac, filter, spraying dry obtains Etimicin sulfate finished product, adds gac 100 grams calculating by every 1 liter of Etimicin sulfate concentrated solution.
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| CN108129527A (en) * | 2018-01-11 | 2018-06-08 | 中国医药集团总公司四川抗菌素工业研究所 | Etimicin derivative and preparation method thereof, its pharmaceutical composition and application |
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| CN104231016B (en) * | 2014-09-30 | 2016-08-24 | 齐鲁天和惠世制药有限公司 | A kind of preparation method of Etimicin sulfate. |
| CN105524129B (en) * | 2015-12-25 | 2018-06-26 | 无锡济民可信山禾药业股份有限公司 | A kind of preparation method of Etimicin Sulfate |
| CN111004291A (en) * | 2019-12-19 | 2020-04-14 | 卓和药业集团有限公司 | Etimicin derivative and synthetic method thereof |
| 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 |
| CN113416118A (en) * | 2021-06-24 | 2021-09-21 | 无锡济煜山禾药业股份有限公司 | Method for recovering solvent methanol in production process of bulk drugs |
| CN114213471A (en) * | 2021-12-27 | 2022-03-22 | 无锡福祈制药有限公司 | Synthesis method of etimicin |
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| CN101723994A (en) * | 2007-10-09 | 2010-06-09 | 常州方圆制药有限公司 | Method for preparing aminoglycoside antibiotic |
| CN102250166A (en) * | 2010-05-21 | 2011-11-23 | 江西济民可信集团有限公司 | Method for preparing Etimicin sulfate |
| CN102746349B (en) * | 2012-06-27 | 2014-07-30 | 常州方圆制药有限公司 | New synthesis method of Etimicin sulfate intermediate 3, 2', 6'-tri-N-acetyl gentamicin Cla |
| CN103113430B (en) * | 2013-03-15 | 2014-11-12 | 齐鲁天和惠世制药有限公司 | Method for preparing etimicin sulfate |
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| CN108129527B (en) * | 2018-01-11 | 2020-03-20 | 中国医药集团总公司四川抗菌素工业研究所 | Etimicin derivative, preparation method thereof, pharmaceutical composition thereof and application thereof |
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| CP01 | Change in the name or title of a patent holder |
Address after: 264000 Shandong Province, Yantai city Zhifu District Tobacco Road No. 1 Patentee after: Fu'an Pharmaceutical Group Yantai only Pharmaceutical Co., Ltd. Address before: 264000 Shandong Province, Yantai city Zhifu District Tobacco Road No. 1 Patentee before: Yantai Justaware Pharmaceutical Co., Ltd. |