CN107652334A - The synthetic method of 3 N ethyl Gentamicin C1as - Google Patents
The synthetic method of 3 N ethyl Gentamicin C1as Download PDFInfo
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- CN107652334A CN107652334A CN201710823129.6A CN201710823129A CN107652334A CN 107652334 A CN107652334 A CN 107652334A CN 201710823129 A CN201710823129 A CN 201710823129A CN 107652334 A CN107652334 A CN 107652334A
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- synthetic method
- diacetyl
- mol ratio
- gentamicinc
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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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The present invention relates to a kind of synthetic method of 3 N ethyl Gentamicin C1as, this method comprises the following steps：By glycol dimethyl ether, HMDS, the concentrated sulfuric acid, 2 ", 6 " N, N diacetyl Gentamicin C1a, which are put into round-bottomed flask, to flow back, the dissolving of question response thing, steam partial solvent.Add dichloromethane to be placed in stirring at 10 DEG C, acetaldehyde is added dropwise.After reaction terminates plus potassium borohydride, borate buffer stirring reaction, normal pressure steam partial solvent.10%~20% sodium hydroxide solution is added, is heated to reflux, is cooled to room temperature, concentrates reaction system.Desalination, pass through the isolated N ethyl Gentamicin C1as of target compound 3.
Description
Technical field
The present invention relates to a kind of organic chemical synthesis method, specifically one kind is with 2 ", 6 " celebrating of-N, N- diacetyl is big
Mycin C1aSynthesize 3-N- ethyl gentamicinCs1aMethod.
Background technology
Etimicin Sulfate is that China scientific research personnel voluntarily develops, and possesses the efficient, less toxic, anti-resistance to of independent intellectual property right
The semi-synthetic aminoglycoside antibiotics of new generation of medicine bacterium, it is unique anti-infectives for obtaining first class national new drug certificate.Its
Preparation Etimicin Sulfate parenteral solution is applied to its sensitive Escherichia coli, Klebsiella pneumoniae, Serratia
Category, citrobacter, Enterobacter, acinetobacter, Proteus, bloodthirsty Bacillus influenzae, Pseudomonas aeruginosa and staphylococcus
The various infection Deng caused by.Clinical studies show this product to below infected with it is preferable the effect of：
Respiratory tract infection：Such as acute bronchitis, AECB, community's pulmonary infection；
Kidney and urogenital infections：Such as acute pyelonephritis, cystitis, chronic pyelonephritis or chronic cystitis
Acute attack etc.；
Skin soft tissue and other infection：Such as skin and soft tissue infection, wound, wound and postpartum of performing the operation infection and its
He infects sensitive bacteria.
Medicine caused adverse reaction in Clinical practice has outside the Pass except the pharmacological activity with medicine in itself, and in medicine
Existing impurity also has very big relation.
3-N- ethyls Gentamicin C1a of the present invention is the master remained in Etimicin Sulfate bulk drug and preparation
One of impurity is wanted, and is most difficult to the impurity obtained, is sold both at home and abroad without the standard items of 3-N- ethyl Gentamicin C1as
Also the document report without correlation.Research process are improved in the quality standard of Etimicin Sulfate bulk drug and its preparation, can not
What is avoided needs to use impurity reference substance.Therefore, the preparation technology of 3-N- ethyl Gentamicin C1as is developed for improving medicine
Quality, the security for improving clinical application are significant.
The content of the invention
It is an object of the invention to provide a kind of 3-N- ethyls gentamicinC1aPreparation method.
Preparation method of the present invention, comprises the following steps：
(1) by glycol dimethyl ether, HMDS and the concentrated sulfuric acid, put into beaker and stir, add 2 ",
6 "-N, N- diacetyl gentamicinC1a, it is heated to reflux, distilling off solvent glycol dimethyl ether；
(2) above-mentioned solution is cooled to 0~10 DEG C, adds dichloromethane, acetaldehyde is added dropwise, ensure solution at 0~10 DEG C
Stirring reaction, potassium borohydride, borate buffer are then added, continue stirring reaction, normal heating concentration；
(3) stirring of 10%-20% sodium hydroxides is added, normal heating distillation, steams partial solvent, is adding 10-20%
Sodium hydroxide solution, it is heated to reflux, is down to room temperature, vacuum filtration obtains filtrate；
(4) desalination, isolated target product 3-N- ethyl gentamicinCs are passed through1a。
Wherein, the HMDS and 2 in step (1) ", the 6 " mol ratios of-N, N- diacetyl Gentamicin C1a
8:1~12:1；The concentrated sulfuric acid and 2 ", 6 "-N, N- diacetyl gentamicinCs1aMol ratio 0.05:1~1.5:1, heating-up temperature
In the 1-3h that flowed back at 80~100 DEG C.
Preferably, the HMDS and 2 in step (1) ", 6 " moles of-N, N- diacetyl Gentamicin C1a
Than 9:1~11:1；The concentrated sulfuric acid and 2 ", 6 "-N, N- diacetyl gentamicinCs1aMol ratio 0.08:1~1.3:1, heating temperature
Degree is in 95 DEG C of backflow 2h.
Wherein, the acetaldehyde and 2 in step (2) ", 6 "-N, N- diacetyl gentamicinCs1aMol ratio 1:1~4:1, boron
The pH value of acid buffering solution regulation solution is to 8~11, potassium borohydride and 2 ", 6 "-N, N- diacetyl gentamicinCs1aMole
Than 4:1~8:1.
Preferably, the acetaldehyde and 2 in step (2) ", 6 "-N, N- diacetyl gentamicinCs1aMol ratio 2:1~3.5:
1, the pH value of borate buffer solution regulation solution is to 10, potassium borohydride and 2 ", 6 "-N, N- diacetyl gentamicinCs1aRub
That ratio 5:1~6.5:1.
Wherein, heating-up temperature is at 110~140 DEG C in step (3), and flow back 20~25h.
Preferably, heating-up temperature is at 125 DEG C in step (3), and flow back 24h.
Wherein, separation is to first pass through macroreticular resin to carry out initial gross separation in step (4), and elution is used as using different concentration ethanol
Agent, then pass through the isolated 3-N- ethyls gentamicinC of silicagel column1a。
Preferably, separation is to first pass through macroreticular resin to carry out initial gross separation in step (4), using different concentration ethanol as washing
De- agent, then pass through the isolated high-purity 3-N- ethyl gentamicinCs of sephadex1a。
It is further preferred that the preparation method of the present invention, comprises the following steps：
(1) in round-bottomed flask is dried equipped with the 100mL of the reflux condensing tube with drying tube, glycol dimethyl ether 6- is put into
10 mL, HMDS 2-8mL, concentrated sulfuric acid 0.01-0.04mL, after stirring, add 2 ", 6 "-N, N- diacetyl
Base gentamicinC1a0.5-2g, it is heated to flowing back, reacts 2h., solvent ethylene glycol diformazan is steamed for distilling apparatus normal heating
Ether；
(2) 0~10 DEG C is cooled to, puts into dichloromethane 5-12mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.1- is added dropwise
0.4mL, 0.5-2h is stirred, add potassium borohydride 0.2-1g, react 0.2-1h, add borate buffer 1-5mL, stir 1-3h；
(3) 10% sodium hydroxide stirring 0.5-2h is added, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent,
20% sodium hydroxide solution 1-4mL is being added, is being heated to reflux 12-48h, is being cooled to room temperature, vacuum filtration obtains filtrate；
(4) filtrate is diluted with salt-free water, is passed through loading in chromatography post, and post, 20-60% ethanol elutions are washed with purifying
Organic phase, concentration, concentrate ammonification water mix, and are passed through loading in chromatography post, collect active ingredient, concentration, and concentrate leads to
Cross and prepare liquid phase process and separated, collect active ingredient, concentration.
3-N- ethyls gentamicinC of the present invention1aSynthetic route, it is as follows：
The preparation method of the present invention, for existing technique, has the advantages that：
The report of 3-N- ethyl Gentamicin C1a correlation synthesis techniques, the present invention are not used as unique 3-N- second at present
The synthesis technique of base Gentamicin C1a, its synthetic route is simple, and operation facility, the used time is short, and cost is low, and environmental pollution is small,
The 3-N- ethyl Gentamicin C1as being prepared by the method for the present invention have the characteristics that purity height and high income, for carrying
High drug quality, the security for improving clinical application are significant.
Brief description of the drawings
Fig. 1, Etimicin Sulfate bulk drug PED detection figure
Fig. 2,3-N- ethyl Gentamicin C1a reference substance PED detection figures
Specific embodiment
By specific examples below, the present invention is further illustrated, but not as the limitation of the present invention
Embodiment 1,3-N- ethyl gentamicinCs1a
A, in round-bottomed flask is dried equipped with the 100mL of the reflux condensing tube with drying tube, glycol dimethyl ether is put into
8mL, HMDS 5mL, concentrated sulfuric acid 0.02mL, after stirring, add 2 ", 6 "-N, N- diacetyl gentamicins
C1a1.0g, it is heated to flowing back, reacts 2h.It is changed to distilling apparatus normal heating and steams solvent ethylene glycol dimethyl ether.
B, 0~10 DEG C is cooled to, puts into dichloromethane 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, adding borate buffer 3mL, (1.0g boric acid adds deionized water 3.0mL stirrings molten
Solution, pH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide stirring 0.5h is added, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.Add
20% sodium hydroxide solution 2mL, is heated to reflux 24h, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography post, washes post with purifying, 40% ethanol elution is organic
Phase, concentration.Concentrate ammonification water mixes, and is passed through loading in chromatography post, collects active ingredient, concentration.Concentrate passes through system
Standby liquid phase is separated according to the big method of medicine, is collected active ingredient, is concentrated to give 3-N- ethyl gentamicinCs1a, its purity is
97%.
Embodiment 2,3-N- ethyl gentamicinCs1a
A, in round-bottomed flask is dried equipped with the 100mL of the reflux condensing tube with drying tube, glycol dimethyl ether is put into
8mL, HMDS 5mL, concentrated sulfuric acid 0.02mL, after stirring, add 2 ", 6 "-N, N- diacetyl gentamicins
C1a1.0g, it is heated to flowing back, reacts 2h.It is changed to distilling apparatus normal heating and steams solvent ethylene glycol dimethyl ether.
B, 0~10 DEG C is cooled to, puts into dichloromethane 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, add borate buffer 3mL (1.0g boric acid adds deionized water 3mL stirring and dissolvings,
PH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide stirring 0.5h is added, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.Add
20% sodium hydroxide solution 2mL, is heated to reflux 24h, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography post, washes post with purifying, 40% ethanol elution is organic
Phase, concentration.Concentrate ammonification water mixes, and is passed through loading in chromatography post, collects active ingredient, concentration.Concentrate passes through silicon
Chloroform, methanol, the ammoniacal liquor of glue post in varing proportions are separated as eluant, eluent, collect active ingredient, concentration, and its purity is
96%.
Embodiment 3,3-N- ethyl gentamicinCs1a
A, in round-bottomed flask is dried equipped with the 100mL of the reflux condensing tube with drying tube, glycol dimethyl ether is put into
8mL, HMDS 5mL, concentrated sulfuric acid 0.02mL, after stirring, add 2 ", 6 "-N, N- diacetyl gentamicins
C1a1.0g, it is heated to flowing back, reacts 2h.It is changed to distilling apparatus normal heating and steams solvent ethylene glycol dimethyl ether.
B, 0~10 DEG C is cooled to, puts into dichloromethane 9mL, then under the conditions of 0~10 DEG C, acetaldehyde 0.2mL is added dropwise, stirs
Mix 1h.Add potassium borohydride 0.5g, react 0.5h, add borate buffer 3mL (1.0g boric acid adds deionized water 3mL stirring and dissolvings,
PH=10 is adjusted with sodium hydroxide), stir 1.5h.
C, 10% sodium hydroxide stirring 0.5h is added, normal heating is distilled to 100 DEG C of liquid temperature, steams partial solvent.Add
20% sodium hydroxide solution 2mL, is heated to reflux 24h, is cooled to room temperature, and vacuum filters to obtain filtrate.
D, filtrate is diluted with salt-free water, is passed through loading in chromatography post, washes post with purifying, 40% ethanol elution is organic
Phase, concentration.Concentrate ammonification water mixes, and is passed through loading in chromatography post, collects active ingredient, concentration.Concentrate passes through Portugal
Polysaccharide gel is separated, and collects active ingredient, concentration, and its purity is 98%.
The Application Example of embodiment 4,3-N- ethyl Gentamicin C1as,
The successful preparation of 3-N- ethyl Gentamicin C1as is with separating, to calculate 3-N- second in Etimicin Sulfate bulk drug
The residual quantity of base Gentamicin C1a provides foundation.
3-N- ethyl Gentamicin C1a 6.56mg are weighed, are diluted to 25mL, take quantitative Etimicin Sulfate bulk drug
It is diluted to 25mL.It can be calculated with following collection of illustrative plates (Fig. 1, Fig. 2) according to data above miscellaneous in Etimicin Sulfate bulk drug
The residual quantity of matter 3-N- ethyl gentamicins is 0.18mg.
Claims (9)
- A kind of 1. 3-N- ethyls gentamicinC1aSynthetic method, it is characterised in that comprise the following steps：(1) by glycol dimethyl ether, HMDS and the concentrated sulfuric acid, put into beaker and stir, add 2 ", 6 "- N, N- diacetyl gentamicinC1a, it is heated to reflux, distilling off solvent glycol dimethyl ether；(2) above-mentioned solution is cooled to 0~10 DEG C, adds dichloromethane, acetaldehyde is added dropwise, ensure that solution stirs at 0~10 DEG C Reaction, potassium borohydride, borate buffer are then added, continue stirring reaction, normal heating concentration；(3) stirring of 10%-20% sodium hydroxides is added, normal heating distillation, steams partial solvent, is adding 10-20% hydrogen-oxygens Change sodium solution, be heated to reflux, be down to room temperature, vacuum filtration obtains filtrate；(4) desalination, isolated target product 3-N- ethyl gentamicinCs are passed through1a。
- 2. synthetic method according to claim 1, it is characterised in that the HMDS and 2 in step (1) ", 6 " mol ratio 8 of-N, N- diacetyl Gentamicin C1a:1~12:1；The concentrated sulfuric acid and 2 ", 6 " celebrating of-N, N- diacetyl is big mould Plain C1aMol ratio 0.05:1~1.5:1, heating-up temperature is in the 1-3h that flowed back at 80~100 DEG C.
- 3. synthetic method according to claim 1, it is characterised in that the HMDS and 2 in step (1) ", 6 " mol ratio 9 of-N, N- diacetyl Gentamicin C1a:1~11:1；The concentrated sulfuric acid and 2 ", 6 " celebrating of-N, N- diacetyl is big mould Plain C1aMol ratio 0.08:1~1.3:1, heating-up temperature is in 95 DEG C of backflow 2h.
- 4. synthetic method according to claim 1, it is characterised in that the acetaldehyde and 2 in step (2) ", 6 "-N, N- diethyls Acyl group gentamicinC1aMol ratio 1:1~4:1, the pH value of borate buffer solution regulation solution to 8~11, potassium borohydride with 2 ", 6 "-N, N- diacetyl gentamicinC1aMol ratio 4:1~8:1.
- 5. synthetic method according to claim 1, it is characterised in that the acetaldehyde and 2 in step (2) ", 6 "-N, N- diethyls Acyl group gentamicinC1aMol ratio 2:1~3.5:1, the pH value of borate buffer solution regulation solution is to 10, potassium borohydride and 2 ", 6 "-N, N- diacetyl gentamicinC1aMol ratio 5:1~6.5:1.
- 6. synthetic method according to claim 1, it is characterised in that heating-up temperature is returned at 110~140 DEG C in step (3) Flow 20~25h.
- 7. synthetic method according to claim 1, it is characterised in that heating-up temperature is at 125 DEG C in step (3), backflow 24h。
- 8. synthetic method according to claim 1, it is characterised in that separation is to first pass through macroreticular resin to enter in step (4) Row initial gross separation, using different concentration ethanol as eluant, eluent, then pass through the isolated 3-N- ethyls gentamicinC of silicagel column1a。
- 9. synthetic method according to claim 1, it is characterised in that separation is to first pass through macroreticular resin to enter in step (4) Row initial gross separation, using different concentration ethanol as eluant, eluent, then pass through the isolated high-purity 3-N- ethyls celebrating of sephadex Big mycin C1a。
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438527A (en) * | 2018-09-20 | 2019-03-08 | 无锡济民可信山禾药业股份有限公司 | A method of recycling Gentamicin C1a from Etimicin sulfate intermediate synthesising by-product |
| CN110066304A (en) * | 2019-05-25 | 2019-07-30 | 无锡济民可信山禾药业股份有限公司 | The synthetic method of 1-N- ethyl micronomicin |
| CN110372760A (en) * | 2019-08-14 | 2019-10-25 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 3-N- ethyl Gentamicin C1a |
| CN110498823A (en) * | 2019-08-14 | 2019-11-26 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 6 "-N- ethyl Gentamicin C1as |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438527A (en) * | 2018-09-20 | 2019-03-08 | 无锡济民可信山禾药业股份有限公司 | A method of recycling Gentamicin C1a from Etimicin sulfate intermediate synthesising by-product |
| CN110066304A (en) * | 2019-05-25 | 2019-07-30 | 无锡济民可信山禾药业股份有限公司 | The synthetic method of 1-N- ethyl micronomicin |
| CN110066304B (en) * | 2019-05-25 | 2022-08-16 | 无锡济煜山禾药业股份有限公司 | Synthesis method of 1-N-ethyl micronomicin |
| CN110372760A (en) * | 2019-08-14 | 2019-10-25 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 3-N- ethyl Gentamicin C1a |
| CN110498823A (en) * | 2019-08-14 | 2019-11-26 | 无锡济民可信山禾药业股份有限公司 | A kind of synthetic method of 6 "-N- ethyl Gentamicin C1as |
| CN110498823B (en) * | 2019-08-14 | 2022-12-06 | 无锡济煜山禾药业股份有限公司 | Synthetic method of 6' -N-ethyl gentamicin C1a |
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