CN111138505B - Preparation method of amikacin - Google Patents
Preparation method of amikacin Download PDFInfo
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- CN111138505B CN111138505B CN202010097356.7A CN202010097356A CN111138505B CN 111138505 B CN111138505 B CN 111138505B CN 202010097356 A CN202010097356 A CN 202010097356A CN 111138505 B CN111138505 B CN 111138505B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
- C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
- C07H15/226—Cyclohexane rings substituted by at least two nitrogen atoms with at least two saccharide radicals directly attached to the cyclohexane rings
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of amikacin, which takes kanamycin A as a starting materialThe raw material is chelated by acetate, and metal ions M are utilized2+The coordination effect of (1) and (3) amino groups is chelated with spatially adjacent hydroxyl groups, namely, the 1-position and 3-position amino groups are protected to reduce the reaction activity of the amino groups, protective groups are introduced into the 3-position and 6 '-position amino groups for protection, then the 1-position amino group and PHBA are selectively subjected to condensation reaction to introduce side chains, then the protective groups of the 3-position and 6' -position amino groups are removed, and finally, the amikacin is obtained through hydrazinolysis reaction and column chromatography purification. The method is simple to operate, has few reaction steps, saves cost, saves energy, protects environment and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a preparation method of amikacin.
Background
Amikacin sulfate is a semisynthetic aminoglycoside antibiotic, has a wide antibacterial spectrum, has strong antibacterial ability on various bacteria, and has obvious effects on treatment of atypical pneumonia and prevention of avian influenza. After the amikacin sulfate is marketed in the last 70 th century, the amikacin sulfate is quickly and widely applied by virtue of the definite curative effect and the unique advantages of low ototoxicity and low nephrotoxicity, and becomes a first-line anti-infective medicament commonly used in clinic in the world. In China, amikacin sulfate has been listed in the national list of cost-saving drugs and is also taken in the category A drugs in the national catalog of basic medical insurance and industrial injury insurance drugs.
Amikacin (Amikacin), also known as Amikacin, chemical name: 1-N- [ L (-) -4-amino-2-hydroxybutyryl]Kanamycin a, molecular formula: c22H43N5O13Molecular weight:585.6, structural formula:
among the currently disclosed methods for the preparation of amikacin, the silanization protection route is most commonly used, and is divided into the persilylation protection (jiang faithful, wangyu. amikacin synthesis method [ J ], fine and chemical specialities, 2004,12(10),26-28) and the partial silanization protection (CN 106866755A). The reaction principle is that the reaction activity of four amino groups is influenced by utilizing the electricity supply property and the steric hindrance effect of the silane group, and a side chain is selectively connected to the amino group at the 1-position, so that the target product amikacin is obtained.
Wherein, the persilylation protection route is as follows: (1) taking kanamycin A as a raw material, and carrying out silanization reaction on 7 hydroxyl groups and 4 amino groups of kanamycin A to obtain silylkanamycin A (compound I); (2) taking gamma-phthalimide group-alpha-hydroxybutyric acid (PHBA) and N-hydroxyphthalimide (NOP) as raw materials, and carrying out dehydration reaction under the action of N, N-Dicyclohexylcarbodiimide (DCC) to prepare active ester (compound II); (3) the amikacin is obtained by taking the silyl kanamycin A and active ester as raw materials and respectively carrying out condensation, hydrolysis and hydrazinolysis reactions. The reaction equation is as follows:
the above route has the following problems: (1) trimethylchlorosilane is easily decomposed in water to form hydrogen chloride, which is harmful to human bodies and can corrode equipment such as a reaction kettle and the like; (2) 7 hydroxyl groups and 4 amino groups of kanamycin A are fully protected, the reaction time is long, the post-treatment is complex, high-temperature and high-vacuum distillation is required, and the time and the labor are consumed; (3) n-hydroxyphthalimide (NOP) is used, and NOP is a high-sensitization substance, so that harm is easily caused to the health of staff in the using process.
In addition, the partial silylation route is: in chinese patent CN106866755A, (1) 7 hydroxyls and 1 amino (6' amino) of kanamycin a are protected by silanization reaction using kanamycin a as raw material to obtain partial silylkanamycin a; (2) a condensation product is obtained by using partial silylkanamycin A and gamma-phthalimide-alpha-hydroxybutyric acid (PHBA) under the action of N, N-Dicyclohexylcarbodiimide (DCC); (3) the condensation product is hydrolyzed, hydrazinolysis reacted and column chromatography purified to obtain amikacin. The reaction equation is as follows:
the above route, although an improvement over the persilylation route, still does not avoid the use of trimethylchlorosilane; and the chemical reaction is mostly acidic or alkaline, and various factors such as instability of the compound can put higher requirements on equipment, so that the production cost is increased.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a novel method for preparing amikacin, which takes kanamycin A as a starting raw material, chelates with acetate and utilizes metal ions M2+The coordination effect of (1) and (3) amino groups is chelated with spatially adjacent hydroxyl groups, namely, the 1-position and 3-position amino groups are protected to reduce the reaction activity of the amino groups, protective groups are introduced into the 3-position and 6 '-position amino groups for protection, then the 1-position amino group and PHBA are selectively subjected to condensation reaction to introduce side chains, then the protective groups of the 3-position and 6' -position amino groups are removed, and finally, the amikacin is obtained through hydrazinolysis reaction and column chromatography purification. The method is simple to operate, has few reaction steps, saves cost, saves energy, protects environment and is more suitable for industrial production.
The technical scheme of the invention is as follows: a preparation method of amikacin is characterized in that,
1) taking kanamycin A as a starting raw material, chelating and protecting 1-position and 3' -position amino groups respectively by acetate in an alcohol solvent to obtain an intermediate A;
2) introducing protecting groups R into amino groups at 3-position and 6' -position of the intermediate A to obtain an intermediate B;
3) then, selectively condensing 1-site amino of the intermediate B and gamma-phthalimide-alpha-hydroxybutyric acid (PHBA) under the action of a condensing agent and a condensing auxiliary agent to obtain a condensation product intermediate C;
4) removing amino protecting groups R at the 3-position and the 6' -position of the intermediate C to obtain an intermediate D; finally, the amikacin is obtained by hydrazinolysis reaction and column chromatography purification.
The reaction equation is as follows:
preferably, the acetate in step 1) is one of copper acetate, zinc acetate, calcium acetate and magnesium acetate. More preferably, the acetate is zinc acetate. The alcohol solvent is methanol, ethanol, isopropanol, etc., preferably methanol.
Preferably, in the step 2), the protecting group R is one of p-nitro carbobenzoxy (PNZ-), carbobenzoxy (CBz-) or fluorenylmethyloxycarbonyl (Fmoc-).
Preferably, the condensing agent in the step 3) is one of Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC) or 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI); the condensation aid is preferably HOBT (1-hydroxybenzotriazole).
The method specifically comprises the following steps:
1) dissolving kanamycin A in methanol serving as a solvent, adding zinc acetate, and reacting at room temperature for 3-6 hours;
2) slowly adding a dichloromethane solution of the protecting group R into the reaction solution, reacting for 1-4 h at room temperature, and performing post-treatment after the reaction is finished to obtain an intermediate B;
3) adding the intermediate B, PHBA and HOBT into a DMF solvent; when the solid is completely dissolved, cooling to 0-5 ℃, and slowly adding a DMF (dimethyl formamide) solution of DCC (DCC); after the addition, slowly heating to room temperature, and reacting for 3-6 h;
4) adding the intermediate C into a mixed solvent of absolute ethyl alcohol and purified water, adding NaOH, raising the temperature to 40-55 ℃, adding sodium bisulfite after the solid is completely dissolved, and reacting for 1-4 hours under the condition of heat preservation after the addition is finished; and after the reaction is finished, carrying out post-treatment to obtain an intermediate D, and finally carrying out hydrazinolysis reaction and column chromatography purification to obtain the amikacin.
Preferably, the molar ratio of kanamycin a to acetate in the step 1) is 1: 3.0 to 6.0.
Preferably, the molar ratio of kanamycin a to the protecting group R in the step 2) is 1: 2.0 to 6.0.
Preferably, the molar ratio of the intermediate B to the gamma-phthalimido-alpha-hydroxybutyric acid (PHBA) in the step 3) is 1: 0.8 to 1.2; the molar ratio of the intermediate B to the condensing agent is 1: 1.0 to 6.0; the molar ratio of the intermediate B to the HOBT is 1: 0.5 to 1.5.
Preferably, the molar ratio of the intermediate C to the sodium hydroxide in the step 4) is 1: 3.0 to 10.0; the molar ratio of the intermediate C to the sodium bisulfite is 1: 5.0 to 15.0.
The post-treatment method of the step 2) comprises the following steps: after the reaction is finished, decompressing and distilling the solvent, and adding dichloromethane and 10% ammonia water into the solid for dissolving; separating, adding sodium chloride into the water phase until the water phase is saturated, then extracting the water phase with isopropanol-dichloromethane (1:1), drying the organic phase, and evaporating the solvent under reduced pressure to obtain an intermediate B.
The post-processing method of the step 3) comprises the following steps: filtering, slowly adding methanol-ammonia water solution (methanol: ammonia water is 10:1) into the filtrate, gradually precipitating solid, filtering, and washing the filter cake to obtain an intermediate C.
The post-treatment method of the intermediate D in the step 4) comprises the following steps: after the reaction is finished, ethanol is evaporated under reduced pressure, the residual liquid is extracted by ethyl acetate, the organic phase is dried, and the solvent is evaporated under reduced pressure to obtain an intermediate D.
The mechanism of the invention is as follows:
as shown above, kanamycin A has 4 amino groups, wherein the amino groups at the 1 position, the 3 position and the 3 'position are shielded by a ring, and the condensation reaction is weaker than the amino group at the 6' position; the 3-amino is induced by ortho hydroxyl, and the activity of condensation reaction is weaker than that of 1-amino and 3-amino; the overall activity sequence was: 6' amino > (3 amino and 1 amino) > 3 "amino. Because the condensation reaction proceeds directly, the 6 ' -amino group is mostly acylated with the product of 6 ' -amino group, and it is necessary to weaken the activity of the 6 ' -amino group and also the 3-and 3 "-amino groups, so that the acylation reaction occurs at the 1-amino group as much as possible. The silanization route utilizes the electricity supply and the steric hindrance effect of the trimethylsilyl group to enable the condensation reaction to occur at the 1-amino position as much as possible, so that a certain effect is achieved, but in terms of actual conditions, the 3-amino condensation product has more impurities, the ratio of the 3-amino condensation product to the 1-amino condensation product is about 1: 2-3, and large material and energy waste is caused.
The invention utilizes the chelating effect of metal ions to form coordinate bonds with electron donating groups (amino and hydroxyl). Wherein, 1-site amino, 6-site hydroxyl and metal ion form coordination, 3-site amino, 4-site hydroxyl and metal ion form coordination, thereby weakening the activity of corresponding amino (1-site and 3-site amino). The 3-site and 6-site amino groups are not easy to form coordinate bonds due to space effect, the amino groups are exposed and have strong activity, and the two amino groups are protected by the structure of an intermediate A shown in the following formula. And then the activity difference of the 1-amino and the 3' -amino is utilized to promote the condensation reaction to be mainly concentrated on the 1-amino, and the amikacin is obtained through hydrazinolysis and column purification.
The invention has the beneficial effects that: the method has short reaction steps, saves cost, saves energy and protects environment; the method has the advantages of simple operation, low cost, no use of easily-degradable reagents and sensitizing reagents, no use of special equipment, low isomer content of the obtained product, high purity (more than or equal to 99.0 percent) and suitability for industrial production of amikacin.
Detailed Description
The present invention will be further described by the following examples, however the scope of the present invention is not limited to the following examples, and technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The structural formula of kanamycin A is shown in the specification
The amikacin is of the structural formula
Example 1:
(1) chelating reaction
Adding 9.68g of kanamycin A and 200ml of methanol into a 500ml reaction bottle, stirring for 0.5h, adding 15.4g of zinc acetate, gradually dissolving the solid, controlling the temperature to be 25-30 ℃, and reacting for 4-5 h.
(2) Amino protection reaction
Slowly adding a mixed solution of 11.78g of PNZ-HOSu and 50ml of dichloromethane into the reaction solution in the previous step, controlling the temperature to be 25-30 ℃ after the addition, and reacting for 2-3 h. After the reaction, the solvent was distilled off from the reaction mixture at 50 ℃ under reduced pressure to obtain a pale yellow solid. 50ml of dichloromethane and 50ml of 10% ammonia water are added to the solid to dissolve; separating, and washing the water phase twice with 20ml of 2 dichloromethane; the organic phases were combined and extracted once with 30ml of 10% ammonia; the aqueous phases were combined and saturated with sodium chloride. The aqueous phase was extracted with 60ml of 3 isopropanol-dichloromethane (1:1), the organic phases were combined, dried over anhydrous sodium sulfate for 1-2 h, filtered, and the solvent was evaporated under reduced pressure to give 13.5g of a pale yellow solid with a purity of 90.08% for intermediate B and an yield of 80.0%.
(3) Condensation reaction
13.5g of intermediate B, 4.78g of PHBA and 2.16g of HOBT were dissolved in 100ml of DMF under stirring. When the solid is completely dissolved, cooling to 0-5 ℃, and slowly adding a mixed solution of 4.95g of DCC and 50ml of DMF within 1 hour; after the addition, slowly heating to 25-30 ℃ and reacting for 4-5 h. After the incubation, the reaction mixture was filtered to remove the solids. 150ml of methanol-ammonia solution (methanol: ammonia 10:1) was slowly added to the filtrate, a solid gradually precipitated, and after the addition, stirring was continued for 1 hour. Filtering, washing the filter cake with 20ml methanol-ammonia water solution (methanol: ammonia water 10:1) to obtain off-white solid 12.2g, namely intermediate C, with purity 88.11% and yield 70.9%.
(4) Deprotection reaction
Adding 12.2g of the intermediate C into 160ml of absolute ethyl alcohol and 80ml of purified water, stirring, adding 2.3g of NaOH solution, stirring, and raising the temperature to 45-50 ℃. And after the solid is basically completely dissolved, adding 9.45g of sodium bisulfite, gradually rendering the reaction solution to be reddish brown, and after the addition is finished, keeping the temperature at 45-50 ℃ for reaction for 2-3 h. After the reaction, ethanol was distilled off under reduced pressure. The remaining liquid was extracted with 100ml x 3 ethyl acetate, the organic phases were combined and dried for 1-2 h. Filtering, and evaporating the solvent under reduced pressure to obtain 7.1g of light yellow solid, namely the intermediate D, with the purity of 92.62 percent and the yield of 87.2 percent.
(5) Hydrazinolysis reaction
Adding 7.1g of the intermediate D and 70ml of acetone into a 250ml reaction bottle, controlling the temperature to be 25-30 ℃, and stirring for dissolving. Slowly adding 6.1g of 80% hydrazine hydrate within half an hour, heating to reflux after the addition is finished, and reacting for 3-4 hours. After the reaction is finished, cooling, adjusting the pH value to 3.0-4.0, filtering, decompressing the filtrate to evaporate the solvent, adsorbing by using CD180 resin, washing by using water, eluting by using 0.12mol/L ammonia water, collecting high-purity amikacin solution, and freeze-drying to obtain 3.4g of white solid, namely amikacin, wherein the purity is 99.33%, the yield is 58.5%, and the total yield is 29.0%.
Example 2:
(1) chelating reaction
Adding 100g of kanamycin A and 2000ml of methanol into a 3000ml reaction bottle, stirring for 0.5h, adding 159g of zinc acetate, gradually dissolving the solid, controlling the temperature to be 25-30 ℃, and reacting for 4-5 h.
(2) Amino protection reaction
A mixture of 182.5g of PNZ-HOSu and 500ml of methylene chloride was slowly added to the reaction solution in the previous step. And after the addition is finished, controlling the temperature to be 25-30 ℃ and reacting for 2-3 h. After the reaction, the solvent was distilled off from the reaction mixture at 50 ℃ under reduced pressure to obtain a pale yellow solid. Adding 500ml of dichloromethane and 500ml of 10% ammonia water into the solid to dissolve; separating, and washing the water phase twice with 200ml of 2 dichloromethane; the organic phases were combined and extracted once with 300ml of 10% ammonia; the aqueous phases were combined and saturated with sodium chloride. The aqueous phase was extracted with 600ml of 3 isopropanol-dichloromethane (1:1), the organic phases were combined, dried over anhydrous sodium sulfate for 1-2 h, filtered, and the solvent was evaporated under reduced pressure to give 135.8g of a pale yellow solid with a purity of 91.25% for intermediate B and a yield of 77.9%.
(3) Condensation reaction
135.8g of intermediate B, 48.1g of PHBA and 22.5g of HOBT were dissolved in 1000ml of DMF under stirring. When the solid is completely dissolved, cooling to 0-5 ℃, and slowly adding 66.4g of DCC in 500ml of DMF solution within 1 hour; after the addition, slowly heating to 25-30 ℃ and reacting for 4-5 h. After the incubation, the reaction mixture was filtered to remove the solids. 1500ml of methanol-ammonia solution (methanol: ammonia 10:1) was slowly added to the filtrate, a solid gradually precipitated, and after the addition, stirring was continued for 1 h. Filtering, washing the filter cake with 200ml methanol-ammonia water solution (methanol: ammonia water 10:1) to obtain 124.9g of off-white solid, namely intermediate C, with the purity of 87.54% and the yield of 72.2%.
(4) Deprotection reaction
Adding 124.9g of intermediate C into 1600ml of absolute ethyl alcohol and 800ml of purified water, stirring, adding 23.2g of NaOH solution, stirring, and raising the temperature to 45-50 ℃. And after the solid is basically completely dissolved, adding 120.9g of sodium bisulfite, gradually rendering the reaction solution to be reddish brown, and after the addition is finished, keeping the temperature at 45-50 ℃ for reaction for 2-3 h. After the reaction, ethanol was distilled off under reduced pressure. The remaining liquid was extracted with 1000ml x 3 ethyl acetate, the organic phases were combined and dried for 1-2 h. Filtration and reduced pressure evaporation of the solvent gave 72.0g of a pale yellow solid, purity 92.89%, yield 86.5%.
(5) Hydrazinolysis reaction
And adding 72.0g of the intermediate D and 750ml of acetone into a 1000ml reaction bottle, controlling the temperature to be 25-30 ℃, and stirring for dissolving. Slowly adding 30.8g of 80% hydrazine hydrate within half an hour, heating to reflux after the addition is finished, and reacting for 3-4 hours. After the reaction is finished, cooling, adjusting the pH value to 3.0-4.0, filtering, decompressing filtrate to evaporate the solvent, adsorbing by using CD180 resin, washing by using water, eluting by using 0.12mol/L ammonia water, collecting high-purity amikacin solution, and freeze-drying to obtain 35.5g of white solid, namely amikacin, with the purity of 99.49%, the yield of 60.3% and the total yield of 29.3%.
Claims (5)
1. A preparation method of amikacin is characterized in that,
1) taking kanamycin A as a starting raw material, and chelating and protecting 1-position and 3' -position amino groups respectively by zinc acetate to obtain an intermediate A;
2) introducing protecting groups R into amino groups at 3-position and 6' -position of the intermediate A to obtain an intermediate B; the protecting group R is one of p-nitro carbobenzoxy, carbobenzoxy or fluorenylmethyloxycarbonyl;
3) then, selectively condensing 1-site amino of the intermediate B and gamma-phthalimide-alpha-hydroxybutyric acid under the action of a condensing agent dicyclohexylcarbodiimide and a condensing aid 1-hydroxybenzotriazole to obtain a condensation product intermediate C;
4) removing amino protecting groups R at the 3-position and the 6' -position of the intermediate C to obtain an intermediate D; finally, performing hydrazinolysis reaction and column chromatography purification to obtain amikacin;
the method specifically comprises the following steps:
1) dissolving kanamycin A in methanol serving as a solvent, adding zinc acetate, and reacting at room temperature for 3-6 hours;
2) slowly adding a dichloromethane solution of the protecting group R into the reaction solution, reacting for 1-4 h at room temperature, and performing post-treatment after the reaction is finished to obtain an intermediate B; the post-processing method comprises the following steps: after the reaction is finished, decompressing and distilling the solvent, and adding dichloromethane and 10% ammonia water into the solid for dissolving; separating liquid, adding sodium chloride into the water phase until the water phase is saturated, then extracting the water phase by using mixed liquid of isopropanol and dichloromethane in a volume ratio of 1:1, drying the organic phase, and distilling the solvent under reduced pressure to obtain an intermediate B;
3) adding the intermediate B, gamma-phthalimide-alpha-hydroxybutyric acid and 1-hydroxybenzotriazole into a solvent DMF; when the solid is completely dissolved, cooling to 0-5 ℃, and slowly adding a DMF solution of dicyclohexylcarbodiimide; after the addition, slowly heating to room temperature, and reacting for 3-6 h;
4) adding the intermediate C into a mixed solvent of absolute ethyl alcohol and purified water, adding NaOH, raising the temperature to 40-55 ℃, adding sodium bisulfite after the solid is completely dissolved, and reacting for 1-4 hours under the condition of heat preservation after the sodium bisulfite is added; and after the reaction is finished, carrying out post-treatment to obtain an intermediate D, and finally carrying out hydrazinolysis reaction and column chromatography purification to obtain the amikacin.
2. The method for preparing amikacin according to claim 1, wherein the molar ratio of kanamycin A to acetate in the step 1) is 1: 3.0 to 6.0.
3. The method for producing amikacin according to claim 1, wherein the molar ratio of kanamycin A to the protecting group R in step 2) is 1: 2.0 to 6.0.
4. The method for preparing amikacin according to claim 1, wherein the molar ratio of the intermediate B to gamma-phthalimido-alpha-hydroxybutyric acid in step 3) is 1: 0.8 to 1.2; the molar ratio of the intermediate B to the dicyclohexylcarbodiimide is 1: 1.0 to 6.0; the molar ratio of the intermediate B to the 1-hydroxybenzotriazole is 1: 0.5 to 1.5.
5. The method of claim 1, wherein the molar ratio of intermediate C to sodium hydroxide in step 4) is 1: 3.0 to 10.0; the molar ratio of the intermediate C to the sodium bisulfite is 1: 5.0 to 15.0.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4297485A (en) * | 1978-11-11 | 1981-10-27 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Production of a selectively protected N-acylated derivative of an aminoglycosidic antibiotic |
| US4902790A (en) * | 1985-10-10 | 1990-02-20 | Pierrel Spa | Novel process for the synthesis of amikacin |
| CN105440090A (en) * | 2014-08-27 | 2016-03-30 | 北大医药重庆大新药业股份有限公司 | A synthetic method of amikacin |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4297485A (en) * | 1978-11-11 | 1981-10-27 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Production of a selectively protected N-acylated derivative of an aminoglycosidic antibiotic |
| US4902790A (en) * | 1985-10-10 | 1990-02-20 | Pierrel Spa | Novel process for the synthesis of amikacin |
| CN105440090A (en) * | 2014-08-27 | 2016-03-30 | 北大医药重庆大新药业股份有限公司 | A synthetic method of amikacin |
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